Discovery of small molecule FLT3 inhibitors that are able to overcome drug-resistant mutations

Guo Zhang; Wenqing Zhang; Chenjian Shen; Jinshan Nan; Ming Chen; Shusheng Lai; Jiemin Zhong; Bolin Li; Tianqi Wang; Yifei Wang; Shengyong Yang; Linli Li

doi:10.1016/j.bmcl.2020.127532

Discovery of small molecule FLT3 inhibitors that are able to overcome drug-resistant mutations

Bioorg Med Chem Lett. 2020 Nov 15;30(22):127532. doi: 10.1016/j.bmcl.2020.127532. Epub 2020 Sep 3.

Authors

Affiliations

¹ State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Sichuan 610041, China.
² Key Laboratory of Drug Targeting and Drug Delivery System of Ministry of Education, West China School of Pharmacy, Sichuan University, Sichuan 610041, China.
³ Guangxi Wuzhou Pharmaceutical Co. Ltd, Wuzhou, Guangxi 543000, China.
⁴ Key Laboratory of Drug Targeting and Drug Delivery System of Ministry of Education, West China School of Pharmacy, Sichuan University, Sichuan 610041, China. Electronic address: lilinli@scu.edu.cn.

PMID: 32891702
DOI: 10.1016/j.bmcl.2020.127532

Abstract

Herein we report the discovery of 1-(5-(tert-butyl)isoxazol-3-yl)-3- (3-fluorophenyl)urea derivatives as new FLT3 inhibitors that are able to overcome the drug resistance mutations: the secondary D835Y and F691L mutations on the basis of the internal tandem duplications (ITD) mutation of FLT3 (FLT3-ITD/D835Y and FLT3-ITD/F691L, respectively). The most potent compound corresponds to 1-(5-(tert-butyl)isoxazol-3-yl)-3-(4-((6,7-dimethoxyquinolin-4-yl)oxy)-3- fluorophenyl)urea (4d), which showed IC₅₀s (half maximal inhibitory concentrations) of 0.072 nM, 5.86 nM and 3.48 nM against FLT3-ITD, FLT3-ITD/F691L and FLT3-ITD/D835Y, respectively. Compound 4d also showed good selectivity for FLT3 in a kinase profiling assay. Collectively, 4d could be a good lead compound and deserves further in-depth studies.

Keywords: Drug-resistant mutation; FLT3; Secondary point mutations; Small molecule inhibitor; Structure-activity relationship.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Cell Line, Tumor
Dose-Response Relationship, Drug
Drug Discovery*
Drug Resistance, Neoplasm / drug effects*
Humans
Molecular Structure
Mutation
Protein Kinase Inhibitors / chemical synthesis
Protein Kinase Inhibitors / chemistry
Protein Kinase Inhibitors / pharmacology*
Small Molecule Libraries / chemical synthesis
Small Molecule Libraries / chemistry
Small Molecule Libraries / pharmacology*
Structure-Activity Relationship
Urea / analogs & derivatives
Urea / chemistry
Urea / pharmacology*
fms-Like Tyrosine Kinase 3 / antagonists & inhibitors*
fms-Like Tyrosine Kinase 3 / genetics
fms-Like Tyrosine Kinase 3 / metabolism

Substances

Protein Kinase Inhibitors
Small Molecule Libraries
Urea
FLT3 protein, human
fms-Like Tyrosine Kinase 3