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

  • Published online on: March 1, 2019     https://doi.org/10.3892/ol.2019.10096
  • Pages: 4735-4741
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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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May-2019
Volume 17 Issue 5

Print ISSN: 1792-1074
Online ISSN:1792-1082

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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