Abstract

Fms-like tyrosine kinase 3 (FLT3) has been verified as a therapeutic target for acute myeloid leukaemia (AML). In this study, we report a series of 2-(1H-indazol-6-yl)-1H-benzo[d]imidazol-5-yl benzamide and phenyl urea derivatives as potent FLT3 inhibitors based on the structural optimisation of previous FLT3 inhibitors. Derivatives were synthesised as benzamide 8a–k, 8n–z, and phenyl urea 8l–m, with various substituents. The most potent inhibitor, 8r, demonstrated strong inhibitory activity against FLT3 and FLT3 mutants with a nanomolar IC₅₀ and high selectivity profiles over 42 protein kinases. In addition, these type II FLT3 inhibitors were more potent against FLT3 mutants correlated with drug resistance. Overall, we provide a theoretical basis for the structural optimisation of novel benzimidazole analogues to develop strong inhibitors against FLT3 mutants for AML therapeutics.

摘要

Fms 样酪氨酸激酶 3 (FLT3) 已被证实为急性髓性白血病 (AML) 的治疗靶点。在这项研究中，我们报告了一系列 2-(1 H -indazol-6-yl)-1 H -benzo[d]imidazol-5-yl 苯甲酰胺和苯基脲衍生物作为有效的 FLT3 抑制剂，基于先前的结构优化FLT3 抑制剂。衍生物被合成为苯甲酰胺8a – k、8n – z和苯基脲8l – m，具有各种取代基。最有效的抑制剂8r表现出对 FLT3 和 FLT3 突变体的强抑制活性，IC _{50为纳摩尔}和超过 42 种蛋白激酶的高选择性谱。此外，这些 II 型 FLT3 抑制剂对与耐药性相关的 FLT3 突变体更有效。总体而言，我们为新型苯并咪唑类似物的结构优化提供了理论基础，以开发针对 AML 治疗的 FLT3 突变体的强抑制剂。