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.
Guo Zhang  1 ,  Wenqing Zhang  2 ,  Chenjian Shen  1 ,  Jinshan Nan  1 ,  Ming Chen  3 ,  Shusheng Lai  3 ,  Jiemin Zhong  3 ,  Bolin Li  3 ,  Tianqi Wang  1 ,  Yifei Wang  2 ,  Shengyong Yang  1 ,  Linli Li  4
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: [email protected].
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.