Progress on quinoline‑based antitumour agents: Mechanistic insights and optimization strategies (Review)

Introduction

Quinoline derivatives are nitrogen-containing aromatic heterocycles consisting of fused benzene and pyridine rings. Since they were first synthesized in the 19th century, quinolines have attracted considerable attention in medicinal chemistry, materials science and biocatalysis given their distinctive electronic properties, namely an extended and polarisable π-conjugated aromatic system formed by fusion of an electron-deficient pyridine ring to a benzene ring, which confers a substantial dipole moment, weak basicity (pKa of the conjugate acid, ~4.9) and a ring nitrogen lone pair available for coordination, hydrogen bonding and π-π stacking, and favourable biocompatibility (1,2). The quinoline scaffold (Fig. 1) confers high molecular stability and lipophilicity, while the coordination capacity of its ring nitrogen facilitates interactions with various biomacromolecules, including DNA, RNA, enzymes and receptors, thereby producing diverse pharmacological activities (1,3–6).

Figure 1. Integrated molecular mechanisms underlying the anticancer activity of quinoline derivatives. Green arrows indicate activating or stimulatory effects, whereas red arrows indicate inhibitory or suppressive effects. Parts of the figure were created Created in BioRender. (BioRender.com/c248457). HDAC, histone deacetylase; Topo, topoisomerase.

In drug discovery and development, quinoline compounds constitute a structurally diverse and functionally versatile class of privileged scaffolds. Their derivatives exhibit notable antibacterial, antimalarial, antiviral, anti-inflammatory and anticancer activities (7). Early representative drugs, such as chloroquine and hydroxychloroquine, exert antimalarial effects by disrupting parasite metabolism (8). Structural modification and expansion of the quinoline scaffold have subsequently led to the development of several anticancer candidates, including ametantrone and lenvatinib, as well as various novel histone deacetylase (HDAC), topoisomerase and EGFR inhibitors (9–11).

Compared with conventional single-target anticancer agents, quinoline derivatives often exhibit synergistic effects across multiple targets. They can directly interfere with key tumour-associated signalling pathways, including PI3K/AKT/mTOR, MAPK/ERK and p53-murine double minute 2 (MDM2), thereby blocking cell-cycle progression and inducing tumour cell apoptosis (12–15). Quinoline scaffolds can also modulate immune responses and autophagy within the tumour microenvironment, indirectly enhancing antitumour immunity (12,16,17). This multilayered pharmacological profile provides quinoline-based compounds with distinct advantages in overcoming drug resistance, improving selectivity and facilitating combination therapies.

The quinoline core is amenable to structural modification. Substituents such as -OCH3, -F, -CF3, -NH2 and -CONH2, together with fused heterocyclic motifs including indoloquinoline, thienoquinoline and quinazoline frameworks, can markedly alter physicochemical properties and target affinity through electronic and steric effects (18). Advances in molecular design and high-throughput screening (HTS) have enabled the generation of extensive quinoline derivative libraries through pharmacophore hybridisation, structure-guided synthesis and artificial intelligence (AI)-assisted design. Several candidates with greater anticancer potential than conventional drugs have subsequently been identified in preclinical studies, including quinoline-indole hybrids that are more potent than 5-fluorouracil in gastric, oesophageal and colon cancer cells (19), quinoline-based EGFR/HER-2 dual inhibitors with nanomolar activity against breast and lung cancer cells (20), 4-phenoxyquinoline c-Met inhibitors that are more cytotoxic than foretinib (21) and combretastatin A-4 quinoline analogues with sub-micromolar antiproliferative activity (22).

Targeted optimisation strategies have also been proposed to address limitations such as poor solubility and relatively high toxicity. For example, constructing dual-responsive quinolinium-based prodrugs through N-methylation enables selective activation by tumour-associated β-glucosidase and H2O2, resulting in tumour-specific drug release, enhanced solubility, increased mitochondrial targeting and reduced systemic toxicity. Similarly, incorporating the quinoline motif into lipid nanoparticles exploits the proton-sponge effect and specific interactions with the lysosomal protein saposin B to improve endosomal escape. This design markedly increases accumulation and the maximum tolerated dose compared with free quinoline compounds (23,24). Concurrently, structural optimisation and activity prediction facilitated by AI and molecular simulation provide powerful tools for the rational design and accelerated screening of quinoline-based agents (25,26).

Collectively, the distinctive structural properties and multi-target regulatory capabilities of quinoline derivatives have established them as a focus of anticancer drug development. Based on a systematic overview of quinoline derivatives structural features and antitumour mechanisms, the present review highlights recent advances in epigenetic regulation, topoisomerase inhibition, signalling pathway modulation, immune and autophagic regulation, structure-activity relationships (SAR), drug-delivery strategies and AI-assisted design. The present review thereby provides insights into the structural optimisation and development of next-generation quinoline-based anticancer agents.

Major antitumour mechanisms of quinoline derivatives

Quinoline derivatives exhibit considerable multitarget and multilayered anticancer properties. Their molecular mechanisms span nuclear-level epigenetic regulation and topoisomerase inhibition, as well as modulation of signalling pathways, immune and autophagy regulation and cytoskeletal targeting (Fig. 1). This integrative regulatory capacity, operating across the nucleus, cytoplasm and signalling networks, confers unique advantages in overcoming tumour heterogeneity, drug resistance and immunosuppression within the tumour microenvironment.

HDAC inhibition

HDAC inhibitors play a critical role in cancer therapy. These compounds directly induce apoptosis in tumour cells and enhance tumour sensitivity to tumour necrosis factor-related apoptosis-inducing ligand, thereby activating apoptotic pathways and producing synergistic anticancer effects (27). HDAC inhibitors can modulate cell-cycle regulation by altering the acetylation of key regulatory elements, including the p21 wild-type p53-activated fragment 1/CDK-interacting protein 1 promoter (28). Several HDAC inhibitors have entered clinical development. For example, vorinostat and romidepsin are used clinically to treat cutaneous T cell lymphoma. These agents exhibit improved pharmacodynamic and pharmacokinetic properties, effectively inhibiting tumour growth, promoting apoptosis and enhancing antiangiogenic activity through regulation of the Janus kinase 2/STAT3/VEGFA signalling axis (29).

To enhance the selectivity and anticancer potency of existing HDAC inhibitors, a range of structural modifications have been introduced into the quinoline scaffold to improve the inhibition of specific HDAC isoforms. A series of newly designed quinoline-indole hybrid compounds have exhibited potent antiproliferative activity against several human cancer cell lines. Among these, 2-chloro-4-(5-methoxy-1H-indol-3-yl) quinoline (compound 1; Fig. 2A) displayed greater antiproliferative activity against MGC-803 gastric cancer, KYSE450 oesophageal cancer and HCT-116 colon cancer cells than the positive control 5-fluorouracil, as indicated by the lower IC50 values of compound 1 (19), although inhibition of individual HDAC isoforms was not assessed in that study. These findings highlight the importance of rational substituent incorporation into the quinoline core for enhancing antitumour potency. In another study, a series of novel 3,4,5-trimethoxyphenyl-quinoline hybrids were designed and synthesised, and several compounds exhibited potent antiproliferative effects against various tumour cell lines. N-[3-(chloromethyl) benzyl]-3,4,5-trimethoxy-N-(quinolin-8-yl) benzamide (compound 2; Fig. 2B) demonstrated strong activity against PC-3 prostate cancer cells, with an IC50 value of 9.23 µmol/l, and induced apoptosis by activating apoptosis-related signalling pathways (30), although its activity against individual HDAC isoforms was not reported.

Figure 2. Structures of (A) Compound 1 [2-chloro-4-(5-methoxy-1H-indol-3-yl) quinoline], (B) Compound 2 [N-(3-(chloromethyl) benzyl)–3,4,5-trimethoxy-N-(quinolin-8-yl) benzamide] and (C) Compound 3[(E)-N-hydroxy-3-(4-(((quinolin-2-ylmethyl)amino)methyl)phenyl)acrylamide].

HDAC inhibitors can also exert antitumour effects by modulating immune responses, and the incorporation of quinoline scaffolds further enhances immune-cell activity within the tumour microenvironment, thereby strengthening antitumour immune responses. Combining HDAC inhibitors with immune checkpoint inhibitors markedly increases the abundance of CD8+ T cells and natural killer (NK) cells within the tumour microenvironment, thereby improving therapeutic responses (31). Certain quinoline derivatives can also upregulate transcription factors such as B-cell lymphoma 6 (Bcl-6), eomesodermin (EOMES), hypoxia-inducible factor 1-α (HIF-1α) and T-box expressed in T cells (T-bet) while activating the AKT/mTOR or NF-κB signalling pathways, ultimately enhancing the cytotoxic activity of CD8+ cytotoxic T lymphocytes (12,32).

Quinoline-based HDAC inhibitors developed through pharmacophore-guided modelling have also demonstrated potent in vitro activity. For example, compound 3 (Fig. 2C) exhibits greater selectivity for HDAC8; it inhibits HDAC8 with an IC50 of 442 nM, substantially lower than that of vorinostat at 7,468 nM, and effectively induces apoptosis, indicating considerable potential for anticancer applications (33).

Future research should focus on developing selective HDAC inhibitors through strategies such as isoform-specific binding pocket-based design, thereby enabling more precise targeting and reducing off-target toxicity (34). Combination strategies integrating HDAC inhibitors with immunotherapy or chemotherapy may also produce synergistic anticancer effects.

Topoisomerase inhibition

Topoisomerase inhibitors play a pivotal role in cancer therapy by disrupting DNA replication and transcription. Their principal therapeutic targets are topoisomerase IIα (Topo IIα) and topoisomerase I (Topo I). Topo IIα is frequently upregulated in tumour cells and represents a key target of several anticancer agents. Drugs such as etoposide and doxorubicin stabilise the covalent Topo IIα-DNA complex, resulting in DNA double-strand breaks and subsequent apoptosis (35,36). Similarly, camptothecin (CPT) and its derivatives, including topotecan and irinotecan, act as Topo I inhibitors by inducing DNA single-strand breaks and exhibit potent clinical antitumour activity against metastatic colorectal and ovarian cancer types (37–39).

As topoisomerases perform essential physiological functions in normal cells, their non-selective inhibition can cause substantial toxicity. Although topoisomerase inhibitors are widely used in cancer therapy, their clinical application is often limited by severe adverse effects and drug resistance. Common toxicities include bone marrow suppression, gastrointestinal toxicity and cardiotoxicity. Such off-target damage can markedly impair patients' quality of life and treatment adherence, thereby restricting the broader clinical application of these agents (40).

Quinoline scaffolds have been investigated for the development of novel topoisomerase inhibitors with improved properties, such as greater aqueous solubility, increased tumour-cell selectivity and reduced toxicity towards non-malignant cells (41). In a previous study, a series of quinoline derivatives bearing phosphorus-containing substituents was synthesised. These compounds exhibited Topo I inhibitory activity comparable to that of the natural inhibitor CPT. Compounds 3, 4 and 5 (Fig. 3A-C) demonstrated pronounced antiproliferative activity against A549 human lung cancer cells and favourable selectivity towards non-malignant MRC5 lung fibroblasts, with no observable toxicity (42). Given the acidic pH of the tumour microenvironment, which typically ranges from 5.7–7.2, tumour-targeting nanocarriers based on poly(2-ethyl-2-oxazoline) have been developed due to their pH sensitivity and versatile terminal structure. This design enables efficient drug release under acidic conditions, enhances cellular uptake and reduces systemic toxicity (43). These strategies may facilitate the clinical translation of quinoline-based topoisomerase inhibitors.

Figure 3. Structures of (A) Compound 4 [(2,4-Bis(4-fluorophenyl)-1,2,3,4-tetrahydroquinolin-8-yl) diphenylphosphine oxide], (B) Compound 5 [(2,4-Bis-(4-fluorophenyl)-1,2,3,4-tetrahydroquinolin-8-yl) diphenylphosphane] and (C) Compound 6 [(2,4-Bis(4-fluorophenyl)-1,2,3,4-tetrahydroquinolin-8-yl)diphenylphosphine sulfide].

Collectively, quinoline derivatives that act as topoisomerase inhibitors induce DNA damage-mediated cytotoxicity and offer potential for synergistic multi-target anticancer therapy.

Regulation of protein kinases and signalling pathways

Aberrant activation of protein kinases is a hallmark of dysregulated tumour signalling networks. Quinoline derivatives can interact with the ATP-binding pocket of kinases, thereby blocking key cancer-related signalling pathways such as EGFR/HER, VEGFR/cellular mesenchymal-epithelial transition factor (c-Met), PI3K/AKT/mTOR, MAPK/ERK and key regulatory axes such as the p53-MDM2 interaction, ultimately exerting potent antitumour effects.

Protein tyrosine kinases (PTKs) and their regulation

PTKs play essential regulatory roles in cellular signalling. By catalysing the transfer of the γ-phosphate group from ATP to tyrosine residues on substrate proteins, PTKs regulate a range of biological processes, including cell proliferation, differentiation, migration and apoptosis (44). Dysregulated PTK activity can aberrantly activate downstream signalling pathways, promote uncontrolled cell proliferation and drive malignant transformation, thereby contributing to cancer development (45). Consequently, PTKs have emerged as major molecular targets in anticancer drug development.

Regulation of the p53/MDM2 pathway

p53 is a central tumour suppressor protein essential for maintaining genomic stability, whereas MDM2 is its principal negative regulator, promoting p53 ubiquitination and degradation (13). Owing to their adaptable molecular recognition scaffold, quinoline derivatives have been widely investigated as potential inhibitors of the p53-MDM2 interaction to restore p53 activity and suppress tumour cell proliferation.

Structure-based virtual screening of a quinoline derivative library identified lead compound 7 (Fig. 4A). Molecular docking indicated that compound 7 occupies the MDM2-binding pocket effectively and has a higher predicted binding affinity than the established inhibitor Nutlin-3, primarily due to strong hydrophobic stacking interactions within the pocket (13). Compound 7 effectively disrupts the p53-MDM2 interaction, with IC50 values of 1.3–9.0 µM, thereby preventing MDM2-mediated p53 degradation and restoring p53 stability and transcriptional activity (14). Reactivation of the p53 pathway subsequently induces cell-cycle arrest and apoptosis in cancer cells. A preclinical study has demonstrated notable in vitro antitumour activity by compound 7, and further investigation is ongoing (14).

Figure 4. Structures of (A) Compound 7 [10-(3-Chlorophenyl)pyrimido [4,5-b][1,8]naphthyridine-2,4(3H,10H)-dithione], (B) Compound 8 [N-(4-(((4-hydroxy-2-oxo-1,2-dihydroquinolin-3-yl) methylene) amino) phenyl) pyrimidine-2-sulfonamide] and (C) Compound 9 [N-(3-Fluoro-4-(6-methoxy-7-(3-(pyrrolidin-1-yl)propoxy)quinolin-4-yloxy) phenyl)-4-oxo-1-(2-(trifluoromethyl) phenyl)-1,4-dihydrocinnoline–3-carboxamide].

Modulation of the MAPK/ERK signalling pathway

The MAPK/ERK cascade is a central driver of tumour progression in hepatocellular carcinoma (HCC) and several other malignancies, such as melanoma, non-small cell lung cancer, colorectal cancer and pancreatic ductal adenocarcinoma. Aberrant activation of the MAPK/ERK cascade accelerates tumour cell proliferation by regulating the AP-1 transcription factor subunits c-JUN (Jun proto-oncogene) and c-FOS (Fos proto-oncogene); it also reduces the expression levels of pro-apoptotic proteins, such as BIM, BAX and BAK, and increases the expression levels of anti-apoptotic genes, such as BCL-2, BCL-xL and MCL-1, thereby enhancing tumour cell survival (46,47). In addition, MAPK/ERK signalling promotes tumour invasion and metastasis by upregulating genes involved in these processes, including matrix metalloproteinase 2 (MMP2), MMP9 and epithelial-mesenchymal transition transcription factors such as SNAIL, SLUG and TWIST (48), stimulating angiogenesis to support nutrient supply and facilitating senescence evasion, allowing tumour cells to maintain sustained proliferative capacity (49). Notably, MAPK/ERK activation in HCC is less commonly driven by RAS or RAF mutations and is instead frequently sustained by alternative mechanisms, including dysregulated upstream receptor activity and reduced expression levels of negative regulators of the pathway, such as the dual-specificity phosphatases DUSP1, DUSP5 and DUSP6 and the Sprouty proteins. Persistent pathway activation is closely associated with tumour progression and poor clinical prognosis (50,51).

Singh et al (15) evaluated a series of quinoline derivatives as potential allosteric MEK1 inhibitors using molecular docking, long-timescale molecular dynamics simulations and molecular mechanics Poisson-Boltzmann surface area free-energy analysis. Absorption, distribution, metabolism, excretion and toxicity profiling and computer-aided toxicity prediction using Toxicity Prediction by Komputer Assisted Technology were also performed to assess drug-likeness and safety. These quinoline derivatives exhibited improved binding stability, stronger predicted affinities and lower predicted toxicity than the reference inhibitors, providing insights into the rational design of low-toxicity anticancer agents.

EGFR inhibitors

Several types of cancer cell, including non-small cell lung cancer, colorectal cancer, glioblastoma and breast cancer cells, depend heavily on EGFR signalling for tumour initiation and progression. EGFR upregulation activates RAS and PI3K pathways, thereby promoting tumour cell proliferation, migration and angiogenesis (52). The first-generation EGFR inhibitors gefitinib and erlotinib inhibit protein tyrosine kinase autophosphorylation and the downstream RAS/RAF/MEK/ERK and PI3K/AKT signalling cascades in EGFR-mutant non-small cell lung cancer cells, resulting in reduced tumour cell proliferation (53).

A series of quinoline-based dual EGFR/HER inhibitors were recently designed and synthesised (20). Among these, compound 8 (Fig. 4B) exhibited particularly potent biological activity. Compound 8 activated caspase-3, caspase-8 and the pro-apoptotic protein Bax while suppressing the expression level of the anti-apoptotic protein Bcl-2, thereby inducing apoptosis in MCF-7 breast cancer and A549 lung cancer cells. Compound 8 demonstrated potent antiproliferative activity against MCF-7 breast cancer and A549 lung cancer cells, with IC50 values of 71 and 31 nM, respectively. These values were lower than that of erlotinib (IC50=80 nM) and comparable to that of lapatinib (IC50=26 nM) (20).

c-Met signalling pathway

c-Met, a receptor tyrosine kinase, is frequently upregulated and aberrantly activated in several types of cancer, including non-small cell lung cancer, gastric cancer, hepatocellular carcinoma and renal cell carcinoma, where it promotes tumour cell proliferation, motility and invasion (21). Two series of 4-phenoxyquinoline-based small-molecule c-Met inhibitors were developed to target this oncogenic pathway. In vitro evaluation demonstrated that most compounds exhibited antiproliferative activity comparable to that of the reference drug foretinib. Among these, lead compound 9 (Fig. 4C) displayed the most promising profile, with greater cytotoxic activity and c-Met inhibition than foretinib (21).

VEGFR-related pathways

VEGFR-2 is frequently upregulated in a range of tumour types, including HCC, colorectal cancer, non-small cell lung cancer and renal cell carcinoma, and represents a key target in antiangiogenic drug development (54). A series of 4(3H)-quinazolinone-derived VEGFR-2 inhibitors were designed and synthesised. Among these, compounds 10, 11 and 12 (Fig. 5A-C) exhibited potent inhibitory activity, with IC50 values of 3.1, 3.4 and 3.7 µM, respectively. Compound 10 markedly suppressed tumour cell proliferation by inducing G2/M-phase arrest and promoting apoptosis. Molecular docking indicated that these compounds had stronger predicted binding affinities for VEGFR-2 than sorafenib. Consistent with these predictions, compounds 10, 11 and 12 exhibited potent antitumour activity in both in vitro assays and animal models (54).

Figure 5. Structures of (A) Compound 10 [2-9(3-Ethyl–4-oxo-3,4-dihydroquinazolin-2-yl)thio0-N-(4-(N-(ethylcarbamothioyl) sulfamoyl-)phenyl) acetamide], (B) Compound 11 [2-((3-Ethyl-4-oxo-3,4-dihydroquinazolin-2-yl) thio)-N-(4-(N-(propylcarbamothioyl) sulfamoyl) phenyl) acetamide] and (C) Compound 12 [N-(4-(N-(Ethylcarbamothioyl) sulfamoyl) phenyl)-2-((4-oxo-3-phenyl-3,4-dihydroquinazolin-2-yl) thio) acetamide].

Several quinoline-based compounds have also entered clinical trials to assess their safety and efficacy in cancer treatment. For example, tivozanib, a potent VEGFR kinase inhibitor, has demonstrated greater therapeutic efficacy than sorafenib in previously treated metastatic renal cell carcinoma in the phase III TIVO-3 trial (ClinicalTrials.gov identifier, NCT02627963) (55).

Coordinated targeting of multiple signalling pathways

Traditional single-target tyrosine kinase inhibitors are a widely used class of cancer treatment; however, their clinical benefits are often limited by poor durability and the rapid emergence of resistance (44). Consequently, increasing attention has focused on multitarget quinoline-based kinase inhibitors that simultaneously modulate several signalling pathways, thereby enhancing antitumour efficacy and reducing compensatory resistance.

Multitarget quinoline-based pathway inhibitors have demonstrated potent antiproliferative and pro-apoptotic activity in diverse cancer models in vitro and in vivo, including glioblastoma and breast cancer cell lines and the corresponding mouse xenograft models. By simultaneously targeting proteins such as EGFR, HER2, mTOR and MDM2, multitarget quinoline-based pathway inhibitors disrupt compensatory signalling mechanisms and may overcome resistance to single-pathway inhibitors. Their therapeutic efficacy may be further enhanced by combination with cytotoxic chemotherapeutic agents. For example, co-administration of an mTOR inhibitor and a G1 to S phase transition 1 (GSPT1) degrader produced synergistic antitumour effects in glioma models, and the dual-target inhibitor YB-3-17, which simultaneously inhibits mTOR and degrades GSPT1, exhibited greater antitumour activity than single-target inhibitors in cellular assays and animal models (56).

Immunomodulatory properties

Beyond their direct effects on tumour cells, quinoline-based compounds can modulate immune function within the tumour microenvironment, thereby enhancing antitumour immune responses (17,32). This immunoregulatory capacity broadens the therapeutic scope of quinoline derivatives and provides new conceptual and mechanistic directions for their use in cancer treatment.

The PI3K/AKT/mTOR signalling cascade is widely activated in multiple malignancies, including breast, colorectal, endometrial, glioblastoma and non-small cell lung cancer, and plays a pivotal role in regulating tumour cell proliferation, metabolism, apoptosis and metastatic behaviour (32). PI3K, an upstream lipid kinase, converts phosphatidylinositol-4,5-bisphosphate into phosphatidylinositol-3,4,5-trisphosphate (PIP3). AKT, the principal downstream effector of PI3K, modulates cell survival, proliferation and metabolism through the phosphorylation of numerous substrates, including glycogen synthase kinase 3β (GSK3β), forkhead box O (FOXO) transcription factors, BCL-2-associated agonist of cell death (BAD), MDM2 and tuberous sclerosis complex 2 (TSC2). mTOR, the mammalian target of rapamycin and a key downstream node of AKT, regulates protein synthesis, cell proliferation and autophagy (57). Genomic alterations, such as mutations or amplifications in phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit α, AKT1 and PTEN, frequently result in aberrant activation of this pathway (32). Dysregulation can also arise from mutations or amplifications in upstream receptor tyrosine kinases, including EGFR, HER2, MET and fibroblast growth factor receptors. By targeting these critical upstream components, quinoline derivatives can reduce the production of tumour-derived immunosuppressive factors and enhance the cytotoxic functions of CD8+ T cells and NK cells. Furthermore, combining these compounds with dendritic cell vaccines, immune checkpoint inhibitors or chimeric antigen receptor-T cell therapies can markedly potentiate antitumour immune responses (32). The immunomodulatory mechanisms of quinoline-based inhibitors acting on different targets are summarised in Table I (58–62).

Table I. Immunomodulatory mechanisms of quinoline-based inhibitors across different molecular targets.

Table I.

Immunomodulatory mechanisms of quinoline-based inhibitors across different molecular targets.

First author/s, year	Inhibitor class	Primary target(s)	Potential immunomodulatory mechanisms	(Refs.)
Arteaga and Engelman, 2014	EGFR inhibitors	EGFR and HER2	EGFR/HER2 signalling plays a central role in tumour cell proliferation and survival. Inhibition of these receptors not only suppresses tumour growth directly but also modifies cytokine and chemokine expression within the tumour micro-environment, thereby affecting immune-cell infiltration and function. EGFR inhibitors may enhance antitumour immunity by reducing tumour-derived immunosuppressive mediators.	(58)
Martorana et al, 2020	MAPK inhibitors	MEK	The MAPK pathway is essential for immune-cell activation and function. MEK inhibition can influence immune-cell proliferation and differentiation, ultimately shaping the immune response. Additionally, suppression of MAPK signalling may reduce inflammatory cytokine production and improve the immune status of the tumour microenvironment.	(59)
Zarin et al, 2023	ALK5 inhibitors	ALK5 (TGF-β receptor I)	TGF-β is an immunosuppressive cytokine that inhibits T cell and NK cell activity while promoting the differentiation of regulatory T cells and myeloid-derived suppressor cells. ALK5 inhibition diminishes TGF-β signalling and can enhance antitumour immunity by increasing CD8+ T cell and NK cell infiltration and activity.	(60)
Zhang et al, 2018	PDGFR inhibitors	PDGFR	PDGFR signalling contributes to tumour angiogenesis and microenvironmental remodelling. Inhibition of PDGFR can reduce angiogenesis, improve oxygen and nutrient delivery and promote immune cell infiltration. Moreover, PDGFR blockade may decrease the recruitment of immunosuppressive cell populations, thereby strengthening antitumour immune responses.	(61)
Byeon et al, 2012	Src inhibitors	Src	Src signalling regulates multiple aspects of immune cell activation, differentiation and function. Src inhibition may modulate immune responses through effects on immune cell proliferation and cytokine production. Reduced Src signalling can also reduce the product of inflammatory cytokines and promote a more favourable immune microenvironment.	(62)

[i] PDGFR, platelet-derived growth factor receptor; NK, natural killer; EGFR, epidermal growth factor receptor; HER2, human EGFR 2; MAPK, mitogen-activated protein kinase; MEK, MAPK/ERK kinase; ALK5, activin receptor-like kinase 5; TGF-β, transforming growth factor-β; Src, proto-oncogene tyrosine-protein kinase Src.

Certain quinoline derivatives can also function as DNA intercalators or alkylating agents, disrupting DNA structure and function, inducing tumour-cell apoptosis and promoting antigen release. This release facilitates immune activation and indirectly strengthens antitumour immunity (63). Collectively, these findings highlight the dual capacity of quinoline-based compounds to exert immunomodulatory and direct antitumour effects, thereby providing multifaceted support for cancer immunotherapy.

The immunomodulatory potential of quinoline derivatives is not limited to inhibition of the PI3K/AKT/mTOR axis. Several compounds can directly engage immune receptors or metabolic checkpoints. Pan et al (64) developed SMUL11R, a chiral toll-like receptor 7 (TLR7) agonist based on an imidazoquinoline scaffold. In HEK Blue hTLR7 cells, SMU-L11-R activated TLR7 with an EC50 of 0.012±0.003 µM. Mechanistic experiments demonstrated that SMUL11R recruits myeloid differentiation primary response 88 (MyD88) and activates MAPK and NF-κB signalling, resulting in the production of TNFα, IL1β and IL6. Treatment with SMU-L11-R also affected macrophage polarisation, increasing the proportion of M1like macrophages from 26.3 to 61.1%. In the MC38 colorectal cancer model, SMUL11R inhibited tumour growth and exerted an additive effect with programmed death-ligand 1 (PD-L1) blockade, which was attributed to enhanced CD8+ T cell infiltration.

He et al (65) identified compound 30, an 8-methoxy-3-cyanoquinoline derivative, as a potent ectonucleotide pyrophosphatase/phosphodiesterase family member 1 (ENPP1) inhibitor. The compound displayed IC50 values of 8.05 nM against ENPP1 and 1.53 nM in MDA-MB-231 triple-negative breast cancer cells, while showing negligible activity against the human ether-à-go-go-related gene potassium channel and a panel of 97 kinases. By blocking cyclic GMP-AMP degradation, compound 30 activated the stimulator of interferon genes pathway. In the same study, compound 30 slowed tumour progression in CT26 colorectal tumour-bearing mice, promoted immune-cell infiltration, increased type I interferon responses and enhanced the efficacy of anti-PD-L1 therapy.

Autophagy-modulating properties

Autophagy is an evolutionarily conserved self-degradative process in which damaged organelles, misfolded proteins and other intracellular components are sequestered within double-membrane autophagosomes and subsequently degraded following fusion with lysosomes. Increasing evidence highlights the dual roles of autophagy in tumour biology and therapeutic response (66,67). Moderate autophagy removes damaged cellular components, maintains cellular homeostasis and protects cells against stress-induced injury. However, excessive autophagy can induce autophagic cell death, which has potential applications in tumour therapy (68).

Certain quinoline derivatives trigger autophagy by suppressing the PI3K/AKT/mTOR signalling pathway, thereby relieving its inhibition of autophagy initiation. Mechanistically, these compounds inhibit PI3K activity and reduce PIP3 generation, resulting in diminished AKT phosphorylation and activation. Subsequent AKT inactivation suppresses mTOR, removes the blockade on autophagy and initiates the autophagic process (66). A notable example is berberine, an isoquinoline alkaloid isolated from Coptis chinensis that has been widely investigated for its anti-inflammatory and anticancer properties. One study demonstrated that berberine induces autophagy and apoptosis by modulating the PI3K/AKT/mTOR axis and regulating reactive oxygen species (ROS) levels, thereby exerting substantial antiproliferative activity across multiple tumour types, including anaplastic thyroid carcinoma, breast cancer, colorectal cancer, lung cancer and hepatocellular carcinoma. Furthermore, berberine exerts strong synergistic effects with doxorubicin in anaplastic thyroid carcinoma cells, markedly enhancing antitumour efficacy without increasing toxicity (67).

Future research should prioritise the development of multitarget quinoline-based autophagy modulators to improve the therapeutic outcomes of patients with cancer and reduce the likelihood of drug resistance.

Microtubule inhibition

Microtubules are essential cytoskeletal components assembled from α- and β-tubulin heterodimers. They participate in numerous cellular processes, including mitotic spindle formation, maintenance of cell morphology, intracellular transport and cell migration. In tumour cells, disruption of microtubule dynamics causes aberrant mitosis, thereby promoting proliferation and metastasis. Microtubule-targeting agents are broadly classified into two categories: i) Microtubule-destabilising agents, such as colchicine microtubulederivatives and vinca alkaloids, which inhibit tubulin polymerisation and promote microtubule depolymerisation; and ii) microtubule-stabilising agents, such as paclitaxel and its analogues, which enhance tubulin polymerisation and stabilise microtubule structures (69).

Previous studies have shown that numerous quinoline-based compounds possess marked microtubule-inhibitory activity and exert antitumour effects by disrupting microtubule dynamics. For example, isoquinoline derivatives inspired by the natural products podophyllotoxin and diphyllin, such as compound 13 (F10; Fig. 6A), effectively inhibit tubulin polymerisation and V-ATPase and induce immunogenic cell death. These compounds exhibit strong antiproliferative activity across four human cancer cell lines and notable tumour-suppressive effects in an RM-1 homograft mouse model (70). A series of novel combretastatin A-4 (CA-4) quinoline derivatives, represented by compound 14 (Fig. 6B), also block tubulin polymerisation, induce G2/M cell-cycle arrest and activate mitochondria-dependent apoptotic pathways, resulting in notable anticancer activity (22). Trifluoromethyl-substituted quinoline derivatives, such as compound 15 (Fig. 6C), target the colchicine-binding site on tubulin, suppress tubulin polymerisation and induce apoptosis, further highlighting the structural advantages of the quinoline scaffold in the design of microtubule-targeting anticancer agents (71).

Figure 6. Structures of (A) Compound 13 [5-bromo-3,6–dimethoxybenzo[1,3]dioxol-4-yl quinazolin-4(3H)-carboxamide], (B) Compound 14 [4-[(2-Methoxy-7-methylquinolin-3-yl)methylene]–2-(3,4,5-trimethoxyphenyl) oxazol-5(4H)-one], (C) Compound 15 [N-(4-aminophenyl)–6-methoxy–N-methyl-2-(trifluoromethyl)-quinoline-4-amine] and (D) Compound 16 [N,N-Dimethyl-3-(3-(dimethylamino)-4–phenylpyrrolo[3,4-b]quinolin-1-yl)–1,2-dihydroquinolin-2-yl) methanamine].

Conventional microtubule-targeting agents, such as paclitaxel, vincristine and vinblastine, are widely used in clinical oncology. However, emerging drug resistance increasingly limits their long-term efficacy (72,73). By contrast, quinoline-based microtubule inhibitors may help overcome resistance owing to their unique electronic structures and multitarget binding properties. Several quinoline derivatives have also been designed to inhibit the aryl hydrocarbon receptor, thereby enhancing their anticancer efficacy. For example, compound 16 (Fig. 6D) remains effective against multidrug-resistant tumour cells and paclitaxel-resistant cell lines, providing a promising strategy for addressing resistance commonly encountered in clinical practice (74). Such multitarget therapeutic approaches can enhance antitumour effects through several mechanisms, including inducing cell-cycle arrest, amplifying apoptotic signalling and strengthening antitumour immune responses.

Despite the promising activity and relatively low toxicity of novel quinoline-based microtubule inhibitors in vitro and in animal models, their safety and potential adverse effects require further evaluation before clinical application. Most quinoline-derived microtubule inhibitors remain at the preclinical stage, and further structural optimisation is required to improve their aqueous solubility and bioavailability.

In summary, quinoline-based compounds exert antitumour effects through multilayered regulatory mechanisms encompassing nuclear processes and cytoskeletal dynamics. These mechanisms include reactivating tumour-suppressor gene expression through HDAC inhibition, disrupting DNA replication and repair by targeting topoisomerases, modulating oncogenic signalling pathways to suppress proliferation and promote apoptosis, improving the tumour microenvironment and enhancing antitumour immunity as well as disrupting cell division by interfering with microtubule dynamics, either by inhibiting tubulin polymerisation at the colchicine-binding site or by promoting microtubule depolymerisation, which leads to G2/M-phase arrest and apoptosis. This multitarget, multipathway and multilevel mode of action distinguishes quinoline derivatives from traditional single-target agents and provides a strong conceptual and mechanistic foundation for their continued optimisation in precision anticancer drug design and combination therapies.

SAR and molecular modification strategies of quinoline derivatives

Quinoline is one of the most distinctive heterocyclic scaffolds and has attracted considerable attention in medicinal chemistry. The quinoline core is an effective anticancer pharmacophore and growing insight into its multitarget antitumour mechanisms has made SAR studies essential for characterising activity profiles and guiding rational optimisation. The type and position of substituents on the quinoline ring, together with the mode of heterocyclic fusion, can notably affect electronic distribution, spatial conformation and target-binding behaviour, thereby determining pharmacological potency and selectivity. Current evidence indicates that the SAR of quinoline derivatives encompasses five principal structural dimensions.

Oxygen-containing substituents: Modulation of activity and selectivity

In EGFR/HER2 dual inhibitors, a methoxy group at the 6-position of the quinoline ring is a key structural feature. Replacing this group with a hydroxyl group (−OH) markedly reduces EGFR inhibitory activity, increasing the IC50 from 0.12 to 2.3 µmol/l (20). Similarly, in tubulin inhibitors derived from colchicine-inspired CA-4 analogues, introducing a methoxy group at the 4-position of the quinoline ring decreases the IC50 from 1.5 to 0.8 µmol/l (22). In HDAC inhibitors containing a 2-aminoquinoline scaffold, ortho-substitution of the aryl moiety with a methoxy group enhances isoform selectivity and reduces off-target inhibition (33).

3,4,5-Trimethoxyphenyl (3,4,5-(OCH3)3).

In HDAC inhibitors derived from an 8-aminoquinoline core, incorporation of a 3,4,5-trimethoxyphenyl group markedly increases lipophilicity and membrane permeability, thereby facilitating cellular uptake. Deletion of any single methoxy group results in an ~40% loss of activity, indicating that the intact trimethoxy motif is indispensable for biological efficacy (30).

Hydroxyl group (−OH)

In colchicine-like tubulin inhibitors, a hydroxyl at the 7-position of the quinoline ring is essential for activity. Loss of this group completely abolishes inhibitory potency, suggesting a critical hydrogen bond with the tubulin binding pocket (71). By contrast, in EGFR inhibitors, replacing the 6-hydroxyl with a methoxy group markedly reduces activity, highlighting the strong target specificity of hydroxyl-mediated interactions (20).

Halogen-containing substituents: Improving stability and metabolic properties

In HDAC inhibitors featuring a 2-aminoquinoline scaffold, a chlorine atom at the 5-position markedly enhances HDAC1 inhibitory activity. For VEGFR-targeted inhibitors, synergistic effects between a 6-chloro group and a 4-piperazinyl substituent exhibit synergistic effects on molecular stability (33).

Fluorine (−F)

Fluorination is commonly associated with enhanced metabolic stability and selectivity in certain quinoline-based series. In EGFR/HER2 dual inhibitors, introducing a fluorine atom ortho to the anilino group improves HER2 selectivity and metabolic stability (20). During the development of c-Met inhibitors, incorporation of a 2-fluorophenoxy group at the 4-position of the quinoline ring decreases the IC50 from 156 to 28 nmol/l, markedly enhancing inhibitory potency (21). However, fluorine substitution has a negligible effect in some tubulin inhibitors, further demonstrating the target-dependent nature of its effects (22,71).

Strong electron-withdrawing groups: Enhancing binding energy and conformational fit

In EGFR/VEGFR-2 dual inhibitors, introduction of a cyano group at the 7-position decreases binding energy from −7.2 to −9.5 kcal/mol, substantially increasing target affinity. As a strong electron-withdrawing group, the cyano group modulates the electron distribution of the quinoline core, improving spatial complementarity and electronic matching with the binding pocket, thereby stabilizing target engagement (75).

Trifluoromethyl group (−CF3)

In the development of colchicine-derived tubulin inhibitors, substitution with a CF3 group at the 2-position increases lipophilicity and intracellular accumulation, yielding an IC50 of 11.2 µmol/l against MCF-7 cells and improving antiproliferative activity (71). Trifluoromethyl groups also enhance the potency and selectivity of Topo I inhibitors through their electron-withdrawing effects (42,76).

Nitrogen-containing substituents: Constructing critical pharmacophores

Anilide fragments can fit into the kinase hinge region. In EGFR/HER2 dual inhibitors, introduction of an anilide at the 4-position of the quinoline core forms a key pharmacophore for hinge-binding in both EGFR and HER2. Additional ortho-substitution (such as fluorine) fine-tunes steric and electronic properties, thereby enhancing target selectivity (20). In c-Met inhibitors, nitrogenous fragments derived from phenoxy motifs exert similar hinge-binding interactions, enabling high-affinity engagement with the c-Met kinase pocket (21).

Carboxamide (−CONH2)

Carboxamide substitution contributes to active-site construction and stabilises protein interactions. In c-Met inhibitors, a 3-position carboxamide on the quinoline core is essential for bioactivity. However, its marked susceptibility to hydrolysis can rapidly abolish antitumour activity, necessitating structural protection strategies such as steric shielding or electronic modulation (21).

Phosphoryl ester groups [-O-PO(OR)2/-N-PO(OR)2]

Phosphoesters improve aqueous solubility and selectivity. In Topo I inhibitors, phosphoester incorporation at the 4-oxygen or 8-nitrogen of quinoline markedly increases solubility (42). Furthermore, the alkoxy chain length on the phosphoester group is positively associated with Topo I inhibitory activity and methyl esters display three-fold higher potency than ethyl analogues. Substitution at the 8-position yields a selectivity index of 8.3 toward HCT116 cells. Specific binding of the phosphoester to Lys48 of Topo I is critical for potent Topo I inhibition and selectivity (42,76).

Heterocyclic substituents: Spatial adaptation and target specificity

In studies of HDAC inhibitors based on a quinolin-2-one scaffold, the introduction of a thiophene-carboxamide group at the 3-position revealed a strong negative association between the size of the heterocycle and HDAC8 inhibitory activity. Compared with furan- or pyridine-based analogues, thiophene-substituted derivatives exhibit superior spatial accommodation within the HDAC8 active pocket and demonstrate markedly enhanced inhibitory potency (34,76).

Indole-fused scaffold

As a fused heterocycle system, the indole can be regarded as a ‘large substituent’. When fused to quinoline in a 1:1 ratio, the resulting system fits precisely into the hydrophobic pocket of p53-MDM2, reducing the IC50 against A549 cells from 23.1 to 7.8 µmol/l and markedly improving potency and selectivity (19).

SAR studies collectively highlight the central role of the quinoline core in shaping antitumour activity and offer mechanistic insights for rational design of novel derivatives. These structure-activity associations provide a systematic knowledge base that informs the rational design priorities discussed in the following section.

Optimization and application strategies for quinoline-based anticancer agents

Building on the aforementioned SAR trends, particularly substituent effects on target affinity, metabolic stability and solubility, this section shifts focus from individual structural determinants to strategic approaches for overcoming pharmacokinetic and formulation barriers, including delivery platforms, prodrug engineering and combination regimens. Despite advances in elucidating the antitumour mechanisms of quinoline derivatives, their clinical translation remains constrained by poor aqueous solubility, low metabolic stability and substantial systemic toxicity. To overcome these limitations, researchers have proposed a comprehensive set of optimization strategies spanning molecular structural design, drug delivery system (DDS) engineering, combination therapy development and AI-assisted screening. These strategies not only improve the pharmacokinetic profiles and target specificity of quinoline derivatives but also provide new avenues for multi-target and individualized precision therapies.

Optimization of DDSs

Although quinoline derivatives exhibit favourable cell membrane permeability, they generally have poor solubility, heterogeneous biodistribution and insufficient target selectivity. Accordingly, DDSs have been widely used to improve the in vivo distribution and controlled release of quinoline derivatives. Nanocarriers typically achieve passive tumour targeting through the enhanced permeability and retention (EPR) effect. Active targeting can also be achieved by modifying the surfaces of quinoline derivative with peptides, antibodies or polysaccharide ligands, such as folic acid, RGD (Arg-Gly-Asp) peptides and anti-HER2 antibodies.

Nanocarrier-based delivery systems

Compared with conventional small-molecule formulations, nanocarrier-based delivery platforms offer notable advantages. Nanocarriers enable passive or active targeting through the physical encapsulation of therapeutic agents, protecting drugs from premature degradation and enhancing their selective accumulation at tumour sites. Quinoline derivatives can be incorporated into nanoparticle cores through hydrophobic interactions, thereby preventing crystallisation and metabolic degradation while enhancing tumour accumulation through the EPR effect (24,77). Liposomes encapsulate quinoline compounds within a phospholipid bilayer, markedly improving their plasma stability and solubility. Polyethylene glycolylated liposomes further reduce non-specific binding to plasma proteins and prolong systemic circulation, making them suitable for long-term treatment regimens (78).

Metallic nanoparticles are also promising carriers for quinoline-based drugs due to their high surface-to-volume ratios, facile surface modification and photothermal properties. For example, keratin-modified biomimetic gold nanoparticles (Ker-AuNPs) can load quinoline derivatives through hydrophobic interactions. The keratin coating improves biocompatibility and strengthens specific interactions with tumour cells. Under near-infrared irradiation, Ker-AuNPs generate heat through surface plasmon resonance, disrupting tumour cell membranes, facilitating drug uptake and enhancing drug-induced ROS production. These effects collectively induce notable tumour cell apoptosis. In vitro studies have shown that this keratin-modified biomimetic gold nanoparticle system exhibits greater tumour cytotoxicity and lower toxicity towards normal cells than free quinoline drugs, indicating its potential for tumour-targeted therapy (79).

A tumour-targeted nanoscale coordination polymer, abbreviated as OX/GC/CQ, has been engineered to co-deliver three therapeutic agents: Oxaliplatin, gemcitabine prodrugs and the quinoline compound, 5-carboxy-8-hydroxyquinoline. Its pH-responsive structure enables selective release of the encapsulated agents within acidic tumour tissues. This nanosystem exerts synergistic antitumour effects by inducing immunogenic cell death in cancer cells and inhibiting PD-L1 expression, thereby alleviating immunosuppression. In vivo experiments using colorectal and triple-negative breast cancer xenograft models demonstrated marked tumour growth inhibition and prolonged animal survival compared with the corresponding control treatments (80).

Receptor-mediated targeted delivery

Targeted delivery to specific cells or tissues can be achieved by introducing functional groups or targeting ligands into the quinoline scaffold. These moieties bind to cell-surface receptors or molecular markers, thereby increasing drug concentrations at the target site. Targeting ligands can selectively bind to receptors upregulated on tumour cells, such as EGFR or HER2. For example, certain quinoline derivatives exert antiproliferative effects on prostate cancer and glioma cells by targeting EGFR (81). Incorporating such ligands promotes drug accumulation within tumour tissues, enhancing therapeutic efficacy while limiting off-target distribution; therefore, receptor-mediated delivery may reduce damage to normal tissues and reduce the incidence of systemic adverse effects.

Prodrug design strategies

Prodrug design represents another key approach to optimising the pharmacokinetic profiles of quinoline derivatives. This strategy involves incorporating ester, amide or disulphide linkages that are cleaved by tumour-specific enzymes or microenvironmental conditions, enabling controlled drug activation and targeted release (82).

Enzyme-responsive prodrugs

The expression or activity of certain enzymes differs markedly between tumour and normal tissues. For example, fibroblast activation protein-α (FAPα) is highly expressed in several types of tumour, including pancreatic, breast, lung and colorectal carcinomas, but expressed at low levels in normal tissues (83). Therefore, enzyme-responsive prodrugs have been developed which remain inactive until they reach the tumour microenvironment, where they are selectively recognised and hydrolysed by FAPα, releasing active quinoline-based drugs for targeted tumour therapy (83).

pH-responsive prodrugs

Tumour tissues typically exhibit an acidic microenvironment, with a lower pH than normal tissues. This feature can be exploited by engineering prodrugs that release active compounds under acidic conditions. Incorporating pH-sensitive chemical bonds into the quinoline scaffold enables bond cleavage within the acidic tumour microenvironment, thereby releasing active quinoline derivatives for targeted tumour treatment (84).

ROS-responsive prodrugs

The redox state of tumour cells differs from that of normal cells and is typically characterised by elevated levels of ROS (85). This difference can be exploited to design prodrugs that are activated under oxidative conditions. For example, incorporating ROS-cleavable groups, such as thioketal linkages, into quinoline derivatives enables prodrug activation within the ROS-rich tumour microenvironment (86).

Structural modification and controlled release optimization

Conjugation of quinoline derivatives can increase molecular polarity and improve water solubility, promoting more uniform in vivo distribution and greater bioavailability (87). Combining the active pharmaceutical ingredient with co-crystal formers can also produce new solid-state forms with improved physicochemical properties. Co-crystals may provide a more stable chemical environment for quinoline derivatives, reducing degradation and preserving their therapeutic performance (88).

Certain quinoline derivatives can enhance intracellular drug uptake by interacting with cell membranes and increasing membrane permeability. Cationic quinoline derivatives interact electrostatically with negatively charged membrane components, promoting endocytosis and intracellular accumulation (89). Similarly, introducing cationic groups into the quinoline scaffold strengthens interactions with cell membranes, thereby improving uptake efficiency and intracellular drug concentrations (90). This strategy may support the development of more effective therapeutic agents.

Prodrug strategies can promote the selective delivery of quinoline derivatives to tumour tissues while limiting their distribution and toxicity in normal tissues, thereby improving overall drug safety. This approach, based on chemical modification, targeted activation and controlled release, may support the clinical translation of quinoline-based therapeutics.

Combination therapy and synergistic treatment strategies

Quinoline derivatives act on multiple signalling pathways and cellular processes, making them suitable for combination therapeutic approaches. Combination therapy not only enhances antitumour efficacy but also helps delay the onset of drug resistance and remodels the tumour microenvironment from an immunosuppressive towards an immune-permissive state.

Synergy with immunotherapy

Owing to their structural flexibility and precise target-binding properties, quinoline derivatives show considerable potential for use in combination with immunotherapy, with well-defined mechanisms of action and broad therapeutic applicability.

Aberrant activation of the PI3K/mTOR pathway in tumour cells frequently contributes to an immunosuppressive microenvironment by restricting cytotoxic T cell infiltration into the tumour core and enhancing the immunosuppressive activity of regulatory T cells, thereby reducing the efficacy of immunotherapy. Quinoline-based PI3K/mTOR inhibitors can selectively block this signalling pathway, suppressing tumour cell proliferation and reversing immunosuppression. These inhibitors promote CD8+ T cell accumulation within the tumour core and restore the activity of suppressed T cells, thereby increasing responsiveness to programmed cell death protein 1/PD-L1 antibodies and enhancing antitumour immunity (66). This strategy has shown potential in several tumour models, including lung cancer and melanoma, by converting immunologically ‘cold’ tumours into ‘hot’ tumours. For example, the quinoline selenocarbamate derivative EI201 inhibits AKT and mTOR phosphorylation and suppresses tumour growth in mouse xenograft models, suggesting potential therapeutic value in immunotherapy-resistant tumours (66,91).

HDACs promote immune evasion by epigenetically masking tumour antigens and impairing immune recognition. Quinoline-derived HDAC inhibitors can reverse this phenotype by upregulating major histocompatibility complex class I (MHC-I) and MHC-II expression on tumour cell surfaces. This effect facilitates antigen uptake and presentation by dendritic cells and enhances T cell-mediated antitumour responses, providing a mechanistic basis for combining quinoline-based HDAC inhibitors with immunotherapy (92).

Synergy with chemotherapy

Quinoline derivatives can be combined with agents acting through distinct mechanisms to achieve synergistic multitarget effects. For example, co-administration with topoisomerase inhibitors enhances the disruption of tumour DNA replication, thereby suppressing tumour cell proliferation (93). Combining drugs that act at different phases of the cell cycle may provide broader inhibition of tumour growth. Co-treatment with quinoline derivatives and CDK inhibitors synergistically induces cell-cycle arrest and inhibits tumour cell proliferation (94).

Combining agents that modulate different signalling pathways may also broaden antitumour activity. For example, combining quinoline derivatives with PI3K/AKT/mTOR pathway inhibitors further suppresses tumour cell proliferation and enhances therapeutic efficacy (12,95). In a phase II clinical trial involving patients with anthracycline-refractory advanced breast cancer, chloroquine combined with taxane-based chemotherapy achieved an objective response rate of 45.16% and a median progression-free survival time of 12.4 months, exceeding the expected response rate of 30% (96).

The recent phase I REVOLUTION platform trial (NCT04787991) evaluated hydroxychloroquine combined with gemcitabine/nab-paclitaxel and ipilimumab in untreated metastatic pancreatic ductal adenocarcinoma. In cohort B, the combination achieved an objective response rate of 40% and a 12-month overall survival rate of 53.9%. Pharmacodynamic analyses demonstrated delayed but sustained increases in activated CD4+ T cells and evidence of autophagy inhibition, suggesting that quinoline-based agents may modulate the tumour immune microenvironment and enhance immune checkpoint inhibitor activity. However, toxicity remained a major concern. Hydroxychloroquine-related adverse effects frequently required dose reductions, resulting in a median relative dose intensity of 60%. Only 2 patients (13%) received >90% of the intended total dose. Grade 3–4 treatment-emergent adverse events occurred in 53% of patients and one grade 5 event involving multiple organ dysfunction syndrome was reported. Consequently, the cohort was not expanded. These findings indicate that quinoline derivatives show promise in combination immunotherapy, although their toxicity and pharmacokinetic properties require improved management in future studies (97).

AI-assisted drug screening and design

In recent years, rapid advances in AI have created new opportunities for drug development and markedly improved the efficiency of quinoline-based compound discovery. Machine learning, deep learning and molecular dynamics simulations can support multiple stages of drug design, including structural optimisation and activity prediction. Advances in AI algorithms, together with improvements in automated HTS platforms, have produced notable synergistic benefits. Studies have shown that AI can process complex drug development datasets to predict compound activity and simulate target binding (25,98).

AI can efficiently analyse large chemical and biological databases containing structural, activity and pharmacokinetic data for tens of thousands of quinoline derivatives, a task that would be impractical to perform manually. Clinical databases, including The Cancer Genome Atlas (TCGA; http://www.cancer.gov/about–nci/organization/ccg/research/structural-genomics/tcga) and the Clinical Proteomic Tumor Analysis Consortium (CPTAC; http://proteomics.cancer.gov/programs/cptac), provide clinically relevant information on quinoline derivative targets, such as cell division cycle 25 (CDC25) and p53-MDM2, supporting the clinical association and validation of AI models. The fused benzene-pyridine scaffold of quinoline is amenable to structural modification. Oxygen-, nitrogen- or halogen-containing substituents can be introduced at positions 6, 7 and 8 to optimise activity. This structural diversity makes quinoline derivatives well suited to AI-driven QSAR modelling and molecular docking, facilitating high-throughput virtual screening and molecular refinement (99).

Compared with conventional discovery pipelines, AI-assisted HTS offers notable gains in efficiency, accuracy and success rates. Conventional workflows depend on the physical synthesis of compound libraries and in vitro validation, which are costly and time-consuming. By contrast, AI-driven virtual screening uses computational simulations for initial compound selection, thereby shortening the discovery cycle. Using Monte Carlo tree search and property-prediction models, researchers evaluated 452 million molecular building blocks within 8.5 h, generated 24,000 complete molecules, selected 58 for synthesis and identified six novel antibacterial compounds with growth-inhibitory activity against the multidrug-resistant Gram-negative pathogen Acinetobacter baumannii, several of which also displayed activity against Escherichia coli, Klebsiella pneumoniae and meticillin-resistant Staphylococcus aureus, corresponding to a hit rate of ~10% (26).

AI-based prediction of patient-specific therapeutic responses may also support personalised cancer treatment by guiding the selection of more precise and effective therapies; therefore, AI has become a practical tool in modern drug development (98). AI-assisted HTS and molecular dynamics simulations are hypothesised to accelerate the development and clinical translation of quinoline-based anticancer agents, advancing data-driven medicinal chemistry.

Overall, optimisation strategies for quinoline derivatives have evolved from simple structural modification towards an integrated framework encompassing prodrug design, targeted delivery platforms and multitarget synergy. The application of AI to molecular generation and activity prediction is accelerating the translation of quinoline compounds from laboratory research to clinical application. These advances provide promising directions and technical support for future clinical development. For comparison, the representative quinoline-based compounds discussed in the present review are summarised in Table II according to their molecular targets, biological activities and clinical development status.

Table II. Summary of quinoline-based compounds included in the present review: Mechanisms, IC50 values and clinical status.

Table II.

Summary of quinoline-based compounds included in the present review: Mechanisms, IC50 values and clinical status.

First author/s, year	Compound	Mechanism of action	IC50 values	Clinical status	(Refs.)
Wang et al, 2021	1	HDAC inhibition (quinoline-indole hybrid)	1.38 µM (MGC-803); 5.34 µM (HCT-116); 5.21 µM (MCF-7)	Preclinical	(19)
Wu et al, 2020	2	HDAC inhibition (trimethoxyphenyl-quinoline hybrid)	9.23 µmol/l (PC-3)	Preclinical	(30)
Chen et al, 2017	3	HDAC8-selective inhibition	442 nM (HDAC8); 72.5 nM (HDAC1); 0.51 µM (K562)	Preclinical	(33)
Alonso et al, 2018	4	Topoisomerase I inhibition	0.25 µM (A549)	Preclinical	(42)
Alonso et al, 2018	5	Topoisomerase I inhibition	0.08 µM (A549)	Preclinical	(42)
Alonso et al, 2018	6	Topoisomerase I inhibition	0.03 µM (A549)	Preclinical	(42)
Dou et al, 2013	7	p53-MDM2 interaction inhibitor	1.3–9.0 µM (binding assay)	Preclinical	(14)
Al-Wahaibi et al, 2024	8	EGFR/HER2 dual inhibitor	71 nM (MCF-7); 31 nM (A549)	Preclinical	(20)
Li et al, 2013	9	c-Met inhibitor	0.59 nM (c-Met); 0.035 µM (A549); 0.022 µM (MKN-45)	Preclinical	(21)
Eissa et al, 2021	10	VEGFR-2 inhibitor	3.1 µM (VEGFR-2); 4.33 µg/ml (HepG-2)	Preclinical	(54)
Eissa et al, 2021	11	VEGFR-2 inhibitor	3.4 µM (VEGFR-2)	Preclinical	(54)
Eissa et al, 2021	12	VEGFR-2 inhibitor	3.7 µM (VEGFR-2)	Preclinical	(54)
Leng et al, 2024	13	Microtubule polymerization inhibitor	Not reported	Preclinical	(70)
Ibrahim et al, 2021	14	Microtubule polymerization inhibitor (CA-4 analogue)	0.010 µM (MCF-7); 0.019 µM (HL-60); 0.022 µM (HCT-116); 0.042 µM (HeLa)	Preclinical	(22)
Zhang et al, 2023	15	Microtubule polymerization inhibitor	11.2 µmol/l (MCF-7)	Preclinical	(71)
Wang et al, 2021	16	Microtubule polymerization inhibitor/AhR antagonist	Not reported (active against MDR cells)	Preclinical	(74)
Pan et al, 2025	SMUL11R	TLR7 agonist (immunomodulatory)	0.012 µM (EC50, HEK Blue hTLR7 cells)	Preclinical	(64)
He et al, 2025	Compound 30	ENPP1 inhibitor (STING pathway activator)	8.05 nM (ENPP1); 1.53 nM (MDA-MB-231)	Preclinical	(65)
Anand et al, 2021	Chloroquine	Autophagy modulator (combination with taxanes)	Not applicable (ORR, 45.16%; median PFS, 12.4 months)	Phase II	(96)
O'Reilly et al, 2026	Hydroxy-chloroquine	Autophagy modulator (combination with chemoimmunotherapy)	Not applicable (ORR, 40%; 12-month OS, 53.9%)	Phase I	(97)
Rini et al, 2020	Tivozanib	VEGFR-1/-2/-3 selective inhibitor	Not applicable (median PFS, 5.6 months vs. 3.9 months for sorafenib; HR=0.73; P=0.016)	Phase III (approved)	(55)

[i] HDAC, histone deacetylase; MDM2, murine double minute 2; c-MET, mesenchymal-epithelial transition factor; CA-4, combretastatin A-4; MDR, multidrug resistance; AhR, aryl hydrocarbon receptor; EC50, half-maximal effective concentration; TLR7, toll-like receptor 7; ENPP1, ectonucleotide pyrophosphatase/phosphodiesterase family member 1; STING, stimulator of interferon genes; ORR, objective response rate; PFS, progression-free survival; OS, overall survival; HR, hazard ratio.

Challenges in the clinical translation of quinoline-based anticancer agents

Although numerous quinoline derivatives have demonstrated potent antitumour activity in preclinical studies, few have progressed to clinical evaluation. Beyond toxicity, clinical translation is hindered by suboptimal pharmacokinetic properties, rapid metabolic clearance, limited tumour selectivity, inadequate biomarker-guided patient stratification and the complexity of designing combination therapies. These challenges highlight the gap between promising preclinical efficacy and successful clinical application.

SGX523 provides an instructive example of the clinical failure of a quinoline derivative. This c-MET receptor tyrosine kinase inhibitor entered clinical development for solid tumours but was discontinued due to unexpected renal toxicity. A mechanistic study revealed that aldehyde oxidase (AO) metabolises SGX523 to 2-quinolinone-SGX523, whose urinary solubility is ~3% that of the parent compound. Urinary concentrations of this metabolite were ~70-fold higher than those of SGX523, supporting the hypothesis that its precipitation within renal tubules causes obstructive nephropathy (100). This toxicity exhibits marked species dependence. The 2-quinolinone metabolite was generated by monkey and human liver S-9 fractions, to a lesser extent by rat S-9 fractions, but not by dog S-9 fractions (100). An inhibition study using raloxifene and hydralazine confirmed that this species-specific metabolism is mediated by AO rather than xanthine oxidase. Humanised-liver chimeric mice have been used to model this toxicity, showing elevated serum creatinine and blood urea nitrogen levels following SGX523 administration, together with tubular accumulation of amorphous material and inflammatory cell infiltration (101). This case illustrates how metabolic liability, rather than intrinsic target toxicity, can determine clinical failure; therefore, early metabolite profiling and species-specific toxicological assessment should be incorporated into the development of future quinoline derivatives.

Cardiotoxicity represents another major concern for quinoline-based compounds. Halofantrine, a quinoline antimalarial, causes marked QT-interval prolongation at therapeutic concentrations and has been associated with sudden death, presumably resulting from malignant ventricular tachyarrhythmias (102). A systematic review of 177 trials involving 35,448 participants receiving quinoline antimalarials recorded no fatal cardiac events in clinical trial settings, although the extent of QT prolongation underscores the need for continued pharmacovigilance (102). Parenteral quinoline formulations, including chloroquine, quinine and quinidine, predictably cause hypotension when administered rapidly and transiently high plasma concentrations may result in cardiovascular collapse; therefore, cardiovascular safety should be addressed during lead optimisation rather than only during late-stage preclinical evaluation, particularly for quinoline derivatives intended for long-term administration.

Quinoline-associated neurotoxicity has been recognised since the early 1970s. Chloroquine and quinine intoxication may cause neuropsychiatric manifestations, including confusion, coma and convulsions (103). In rats, subacute exposure to diiodohydroxyquinoline induces motor and sensory abnormalities, with histopathological examination revealing degeneration and demyelination in the cerebral cortex, striatum, spinal cord and sciatic nerve. Young female rats demonstrate greater susceptibility, indicating that age and sex may be predisposing factors (103). At the neuromuscular junction, quinine, quinidine and chloroquine reduce the quantal content of end-plate potentials by 37–45% at clinically relevant concentrations (5×10−5 M). These compounds affect presynaptic and postsynaptic transmission through open- and closed-channel blockade of acetylcholine receptors (104); therefore, neurological safety should be considered when optimising quinoline-based therapeutics, particularly compounds capable of penetrating the central nervous system.

Genotoxicity and carcinogenic risk also warrant attention. Quinoline is a well-established hepatocarcinogen in rats and mice; it exhibits mutagenic activity in Salmonella typhimurium TA100 following metabolic activation and induces placental glutathione S-transferase-positive foci in rat liver (105). However, structure-activity studies have identified opportunities to reduce these risks through structural modification (105,106). For example, 3-fluoroquinoline is neither mutagenic in bacterial tester strains nor carcinogenic in newborn mice; however, 5-fluoroquinoline retains both properties (106). This positional specificity suggests that fluorination at the 3-position may provide an antimutagenic and anticarcinogenic modification, presumably by inhibiting enzymatic epoxidation of the 2,3-double bond, which generates the ultimate mutagenic enamine epoxide intermediate (105). Studies in newborn mice have further shown that quinoline induces HCC, whereas certain benzoquinoline isomers lack carcinogenic activity under the same conditions (106,107). These findings provide a rational basis for designing safer quinoline derivatives and demonstrate that scaffold modification can reduce toxicological liabilities while preserving therapeutic activity.

Despite these challenges, quinoline derivatives retain considerable therapeutic potential. The identification of 3-fluoroquinoline as a non-genotoxic and non-carcinogenic analogue demonstrates that carefully designed structural modifications can eliminate specific toxicological liabilities. The SGX523 case also highlights the importance of early AO metabolism assessment and species-appropriate toxicological modelling. Together with continued structural optimisation and formulation development, these insights offer viable approaches to mitigating the remaining barriers to clinical translation. The development of quinoline-based anticancer therapeutics should consider antitumour potency alongside metabolic stability, safety, pharmacokinetic behaviour and patient stratification. Integrating these factors into medicinal chemistry optimisation will be essential for translating the promising biological activity of quinoline scaffolds into clinically successful anticancer therapies.

Conclusions and future perspectives

As an essential scaffold in anticancer drug research, quinoline combines a fused-ring architecture with an intramolecular nitrogen atom, conferring structural stability and strong target-binding affinity. Structural modification and functionalisation enable quinoline derivatives to modulate several hallmarks of tumour development, including DNA topology, signalling pathways, autophagy and immune remodelling. This multitarget activity may enhance the antitumour efficacy of these derivatives relative to traditional single-target agents. Nanodelivery systems and prodrug strategies can improve the pharmacokinetic properties of quinoline derivatives and reduce toxicity, while combination therapies offer potential to enhance efficacy and limit drug resistance. AI technologies and computational modelling also provide valuable tools for screening, optimising and designing new quinoline derivatives.

However, several challenges remain. The metabolic stability, solubility and toxicity of the quinoline core require further optimisation; its intrinsic multitarget activity also demands careful balancing of therapeutic selectivity and toxicity. Most newly developed candidates remain at the preclinical stage, with limited clinical translation and insufficient systematic evaluation of safety and long-term efficacy. Future research should systematically validate multitarget mechanisms, optimise the safety and controllability of prodrug and delivery systems as well as establish closed-loop drug-design pipelines integrating AI with experimental validation.

In summary, quinoline derivatives constitute a valuable and versatile structural class in medicinal chemistry with broad development potential. Research has progressed from fundamental structural studies towards intelligent drug-design paradigms. The potential applications of quinoline derivatives in precision medicine and personalised therapy may support further innovation in anticancer drug development and improve clinical outcomes.

Acknowledgements

Not applicable.

Funding

This study was financially supported by the National Natural Science Foundation of China (grant no. 32503103).

Availability of data and materials

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Authors' contributions

YZe and YY contributed equally to the conception and design of the review, performed the literature search, screened the articles, extracted and synthesized the data and drafted the initial manuscript. SW, WW and KC participated in the literature search and assisted with figure and table preparation, and reviewed and edited the manuscript. YL, QY and NZ critically revised and proofread the manuscript. YZh secured the funding, supervised the study, resolved discrepancies in study selection and data interpretation and provided critical revision of the manuscript. All authors read and approved the final version of the manuscript. Data authentication is not applicable.

Ethics approval and consent to participate

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Patient consent for publication

Not applicable.

Competing interests

The authors declare that they have no competing interests.

Use of artificial intelligence tools

During the preparation of this work, artificial intelligence tools (ChatGPT 5.2; http://chatgpt.com) were used to improve the readability and language of the manuscript or to generate images, and subsequently, the authors revised and edited the content produced by the artificial intelligence tools as necessary, taking full responsibility for the ultimate content of the present manuscript.

References