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Article

Discovery of LDD‑1075 as a potent FLT3 inhibitor

  • Authors:
    • Kyoung Bin Yoon
    • Hyo Jeong Lee
    • Hye Jin Chung
    • Jungeun Lee
    • Jungil Choi
    • Jeong Doo Heo
    • Yong‑Chul Kim
    • Sun‑Young Han
  • View Affiliations / Copyright

    Affiliations: College of Pharmacy and Research Institute of Pharmaceutical Sciences, Gyeongsang National University, Jinju, Gyeongsangnam-do 52828, Republic of Korea, School of Life Sciences, Gwangju Institute of Science and Technology, Gwangju 61005, Republic of Korea, Gyeongnam Department of Environmental Toxicology and Chemistry, Korea Institute of Toxicology, Jinju, Gyeongsangnam-do 52834, Republic of Korea
  • Pages: 4735-4741
    |
    Published online on: March 1, 2019
       https://doi.org/10.3892/ol.2019.10096
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Abstract

Fms‑like tyrosine kinase 3 (FLT3) is a valuable pharmacological target in the treatment of acute myeloid leukemia (AML). LDD‑1075 and LDD‑1076 are indirubin derivatives, and LDD‑1075 is the ester form of LDD‑1076. LDD‑1076 exhibited a potent in vitro FLT3 kinase activity inhibition with an IC50 of 7.89 nM, whereas, LDD‑1075 demonstrated a relatively weak activity against FLT3 (IC50 of 3.19 µM). In contrast with the results of the FLT3 kinase activity inhibition assay, the LDD‑1076 did not affect the growth of the MV4‑11 cell line, which harbors the constitutively activated form of the FLT3 mutation. Notably, LDD‑1075 exhibited a strong cytotoxic effect against the MV4‑11 cells. When LDD‑1075 was incubated with the MV4‑11 cell lysate, the formation of LDD‑1076 was observed. Treatment with LDD‑1075 inhibited the FLT3 phosphorylation along with the phosphorylation of the signal transducer and activator of transcription 5 protein, which is a downstream signal transducer of FLT3. Treatment with LDD‑1075 induced apoptosis and cell cycle arrest at the G1 phase. The present study demonstrated that the LDD‑1076 formed by the bioconversion of LDD‑1075 is a potent FLT3 inhibitor with anti‑leukemic activity.
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Copy and paste a formatted citation
Spandidos Publications style
Yoon KB, Lee HJ, Chung HJ, Lee J, Choi J, Heo JD, Kim YC and Han SY: Discovery of LDD‑1075 as a potent FLT3 inhibitor. Oncol Lett 17: 4735-4741, 2019.
APA
Yoon, K.B., Lee, H.J., Chung, H.J., Lee, J., Choi, J., Heo, J.D. ... Han, S. (2019). Discovery of LDD‑1075 as a potent FLT3 inhibitor. Oncology Letters, 17, 4735-4741. https://doi.org/10.3892/ol.2019.10096
MLA
Yoon, K. B., Lee, H. J., Chung, H. J., Lee, J., Choi, J., Heo, J. D., Kim, Y., Han, S."Discovery of LDD‑1075 as a potent FLT3 inhibitor". Oncology Letters 17.5 (2019): 4735-4741.
Chicago
Yoon, K. B., Lee, H. J., Chung, H. J., Lee, J., Choi, J., Heo, J. D., Kim, Y., Han, S."Discovery of LDD‑1075 as a potent FLT3 inhibitor". Oncology Letters 17, no. 5 (2019): 4735-4741. https://doi.org/10.3892/ol.2019.10096
Copy and paste a formatted citation
x
Spandidos Publications style
Yoon KB, Lee HJ, Chung HJ, Lee J, Choi J, Heo JD, Kim YC and Han SY: Discovery of LDD‑1075 as a potent FLT3 inhibitor. Oncol Lett 17: 4735-4741, 2019.
APA
Yoon, K.B., Lee, H.J., Chung, H.J., Lee, J., Choi, J., Heo, J.D. ... Han, S. (2019). Discovery of LDD‑1075 as a potent FLT3 inhibitor. Oncology Letters, 17, 4735-4741. https://doi.org/10.3892/ol.2019.10096
MLA
Yoon, K. B., Lee, H. J., Chung, H. J., Lee, J., Choi, J., Heo, J. D., Kim, Y., Han, S."Discovery of LDD‑1075 as a potent FLT3 inhibitor". Oncology Letters 17.5 (2019): 4735-4741.
Chicago
Yoon, K. B., Lee, H. J., Chung, H. J., Lee, J., Choi, J., Heo, J. D., Kim, Y., Han, S."Discovery of LDD‑1075 as a potent FLT3 inhibitor". Oncology Letters 17, no. 5 (2019): 4735-4741. https://doi.org/10.3892/ol.2019.10096
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