Article
Author: Liu, Jia-Chuan ; Yu, Yan-Cheng ; Li, Qing-Qing ; Cheng, Yang ; Li, Nian-Guang ; Leng, Xue-Jiao ; Ding, Ning ; Xu, Yu-Jing ; Yang, Jin ; Dai, Wei-Chen ; Wei, Tian-Hua ; Lu, Meng-Yi ; Zhang, Meng-Yuan ; Chen, Zi-Jun ; Wang, Xiao-Long ; Sun, Shan-Liang ; Yang, Ye ; Kang, Ji-Bo ; Xue, Xin ; Cai, Jiao ; Shi, Zhi-Hao ; Ni, Xing-Feng ; Wang, Zi-Xuan ; Li, Nan
The FLT3-ITD (internal tandem duplication) mutant has been a promising target for acute myeloid leukemia (AML) drug discovery but is now facing the challenge of resistance due to point mutations. Herein, we have discovered a type II FLT3 inhibitor, SILA-123. This inhibitor has shown highly potent inhibitory effects against FLT3-WT (IC50 = 2.1 nM) and FLT3-ITD (IC50 = 1.0 nM), tumor cells with the FLT3-ITD mutant such as MOLM-13 (IC50 = 0.98 nM) and MV4-11 (IC50 = 0.19 nM), as well as BaF3 cells associated with the FLT3-ITD mutant and point mutations like BaF3-FLT3-ITD-G697R (IC50 = 3.0 nM). Moreover, SILA-123 exhibited promising kinome selectivity against 310 kinases (S score (10) = 0.06). In in vivo studies, SILA-123 significantly suppressed the tumor growth in MV4-11 (50 mg/kg/d, TGI = 87.3%) and BaF3-FLT3-ITD-G697R (50 mg/kg/d, TGI = 60.0%) cell-inoculated allograft models. Our data suggested that SILA-123 might be a promising drug candidate for FLT3-ITD-positive AML.