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

Daseul Im; Joonhong Jun; Jihyun Baek; Haejin Kim; Dahyun Kang; Hyunah Bae; Hyunwook Cho; Jung-Mi Hah

doi:10.1080/14756366.2021.2020772

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

J Enzyme Inhib Med Chem. 2022 Dec;37(1):472-486. doi: 10.1080/14756366.2021.2020772.

Authors

Daseul Im^{1

2}, Joonhong Jun^{1

2}, Jihyun Baek^{1

2}, Haejin Kim^{1

2}, Dahyun Kang^{1

2}, Hyunah Bae^{1

2}, Hyunwook Cho^{1

2}, Jung-Mi Hah^{1

2}

Affiliations

¹ Department of Pharmacy, College of Pharmacy, Hanyang University, Ansan, Korea.
² Institute of Pharmaceutical Science and Technology, Center for Proteinopathy, Hanyang University, Ansan, Korea.

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.

Keywords: Benzimidazole; FLT3; FLT3-D835Y; FLT3-ITD; Indazole.

MeSH terms

Benzimidazoles / chemical synthesis
Benzimidazoles / chemistry
Benzimidazoles / pharmacology*
Crystallography, X-Ray
Dose-Response Relationship, Drug
Drug Design*
Humans
Models, Molecular
Molecular Structure
Mutation
Protein Kinase Inhibitors / chemical synthesis
Protein Kinase Inhibitors / chemistry
Protein Kinase Inhibitors / pharmacology*
Structure-Activity Relationship
fms-Like Tyrosine Kinase 3 / antagonists & inhibitors*
fms-Like Tyrosine Kinase 3 / genetics
fms-Like Tyrosine Kinase 3 / metabolism

Substances

Benzimidazoles
Protein Kinase Inhibitors
FLT3 protein, human
fms-Like Tyrosine Kinase 3

Grants and funding

This work was financially supported by National Research Foundation of Korea grants NRF-2019M3A9A8066500 (J.-M. Hah), NRF-2020R1A6A1A03042854 (Center for Proteinopathy), and NRF-2021R1A2C2007159 (J.-M. Hah), and was supported by an Institute of Information & Communications Technology Planning & Evaluation (IITP) grant funded by the Korean government (MSIT) (No.2020–0-01343, Hanyang University ERICA Artificial Intelligence Convergence Research Center).