化学
吲唑
蛋白激酶结构域
酪氨酸激酶
髓系白血病
激酶
受体酪氨酸激酶
癌症研究
分子生物学
突变体
生物化学
生物
信号转导
立体化学
基因
作者
Bongki Ko,Yun Hee Jang,Min Ha Kim,Thai Thi Lam,Hye Kyung Seo,Pyeonghwa Jeong,Munkyung Choi,Keon Wook Kang,So‐Deok Lee,Jin Hee Park,Myung-Jin Kim,Sun‐Young Han,Yong‐Chul Kim
标识
DOI:10.1016/j.ejmech.2023.115860
摘要
The FMS-like tyrosine kinase 3 (FLT3) gene encodes a class III receptor tyrosine kinase that is expressed in hematopoietic stem cells. The mutations of FLT3 gene found in 30% of acute myeloid leukemia (AML), leads to an abnormal constitutive activation of FLT3 kinase of the receptor and results in immature myeloblast cell proliferation. Although small molecule drugs targeting the FLT3 kinase have been approved, new FLT3 inhibitors are needed owing to the side effects and drug resistances arising from kinase domain mutations, such as D835Y and F691L. In this study, we have developed benzimidazole-indazole based novel inhibitors targeting mutant FLT3 kinases through the optimization of diverse chemical moieties substituted around the core skeleton. The most optimized compound 22f exhibited potent inhibitory activities against FLT3 and FLT3/D835Y, with IC50 values of 0.941 and 0.199 nM, respectively. Furthermore, 22f exhibited strong antiproliferative activity against an AML cell line, MV4-11 cells with a GI50 of 0.26 nM. More importantly, 22f showed single-digit nanomolar GI50 values in the mutant FLT kinase expressed Ba/F3 cell lines including FLT-D835Y (GI50 = 0.29 nM) and FLT3-F691L (GI50 = 2.87 nM). Molecular docking studies indicated that the compound exhibits a well-fitted binding mode as a type 1 inhibitor in the homology model of active conformation of FLT3 kinase.
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