2. Academic Validation
  3. Discovery of small molecule FLT3 inhibitors that are able to overcome drug-resistant mutations

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

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.

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