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ID: ALA4028866
Journal: J Med Chem
Title: Discovery of 1-(4-(4-Amino-3-(4-(2-morpholinoethoxy)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)phenyl)-3-(5-(tert-butyl)isoxazol-3-yl)urea (CHMFL-FLT3-213) as a Highly Potent Type II FLT3 Kinase Inhibitor Capable of Overcoming a Variety of FLT3 Kinase Mutants in FLT3-ITD Positive AML.
Authors: Wang A, Li X, Chen C, Wu H, Qi Z, Hu C, Yu K, Wu J, Liu J, Liu X, Hu Z, Wang W, Wang W, Wang W, Wang L, Wang B, Liu Q, Li L, Ge J, Ren T, Zhang S, Xia R, Liu J, Liu Q.
Abstract: FLT3-ITD mutant has been observed in about 30% of AML patients and extensively studied as a drug discovery target. On the basis of our previous study that ibrutinib (9) exhibited selective and moderate inhibitory activity against FLT3-ITD positive AML cells, through a structure-guided drug design approach, we have discovered a new type II FLT3 kinase inhibitor, compound 14 (CHMFL-FLT3-213), which exhibited highly potent inhibitory effects against FLT3-ITD mutant and associated oncogenic mutations (including FLT3-D835Y/H/V, FLT3-ITD-D835Y/I/N/A/G/Del, and FLT3-ITD-F691L). In the cellular context 14 strongly affected FLT3-ITD mediated signaling pathways and induced apoptosis by arresting cell cycle into G0/G1 phase. In the in vivo studies 14 demonstrated an acceptable bioavailability (F = 19%) and significantly suppressed the tumor growth in MV4-11 cell inoculated xenograft model (15 mg kg-1 day-1, TGI = 97%) without exhibiting obvious toxicity. Compound 14 might be a potential drug candidate for FLT3-ITD positive AML.
CiteXplore: 28956923