Rational design and synthesis of 2-(1H-indazol-6-yl)-1H-benzo[d]imidazole derivatives as inhibitors targeting FMS-like tyrosine kinase 3 (FLT3) and its mutants

被引：6

作者：

Im, Daseul ^{[1
,2
]}

Jun, Joonhong ^{[1
,2
]}

Baek, Jihyun ^{[1
,2
]}

Kim, Haejin ^{[1
,2
]}

Kang, Dahyun ^{[1
,2
]}

Bae, Hyunah ^{[1
,2
]}

Cho, Hyunwook ^{[1
,2
]}

Hah, Jung-Mi ^{[1
,2
]}

机构：

[1] Hanyang Univ, Coll Pharm, Dept Pharm, 55 Hanyandaehak Ro, Ansan, South Korea

[2] Hanyang Univ, Ctr Proteinopathy, Inst Pharmaceut Sci & Technol, Ansan, South Korea

来源：

JOURNAL OF ENZYME INHIBITION AND MEDICINAL CHEMISTRY | 2022年 / 37卷 / 01期

基金：

新加坡国家研究基金会;

关键词：

FLT3; FLT3-ITD; FLT3-D835Y; Benzimidazole; Indazole; ACUTE MYELOID-LEUKEMIA; DISCOVERY; MUTATIONS; ANALOGS;

D O I：

10.1080/14756366.2021.2020772

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

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.

引用

页码：472 / 486

页数：15

共 28 条

[1]

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