State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Sichuan 610041, China.
Key Laboratory of Drug Targeting and Drug Delivery System of Ministry of Education, West China School of Pharmacy, Sichuan University, Sichuan 610041, China.
Bioorg Med Chem Lett. 2020 Nov 15;30(22):127532. doi: 10.1016/j.bmcl.2020.127532. Epub 2020 Sep 3.
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 ICs (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.
在此，我们报告了一系列新型 FLT3 抑制剂的发现，这些抑制剂是 1-(5-(叔丁基)异恶唑-3-基)-3-(3-氟苯基)脲衍生物，能够克服 FLT3 上的耐药突变：基于 FLT3 内部串联重复（ITD）突变的继发性 D835Y 和 F691L 突变（分别为 FLT3-ITD/D835Y 和 FLT3-ITD/F691L）。最有效的化合物是 1-(5-(叔丁基)异恶唑-3-基)-3-(4-((6,7-二甲氧基喹啉-4-基)氧基)-3-氟苯基)脲（4d），对 FLT3-ITD、FLT3-ITD/F691L 和 FLT3-ITD/D835Y 的 IC50（半最大抑制浓度）分别为 0.072 nM、5.86 nM 和 3.48 nM。化合物 4d 在激酶谱分析测定中对 FLT3 也表现出良好的选择性。总的来说，4d 可能是一个很好的先导化合物，值得进一步深入研究。
