Structure-Based Design and Optimization of Novel, Potent and Selective Covalent FGFR2/3 Inhibitors with a Tricyclic
Xuzhi Lu1,2, Zhaodi Tian2,3, Xueqiang Li4
1International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Discovery of Chinese Ministry of Education (MOE), Guangzhou City Key Laboratory of Precision Chemical Drug Development, College of Pharmacy, Jinan University, 855 Xingye Avenue East, Guangzhou 511400, China.
Abstract:
Fibroblast growth factor receptors 2 and 3 (FGFR2/3) are attractive therapeutic targets in multiple human cancers. Here, we report the discovery of a series of tricyclic 1-(4-amino-5-ethynyl-8,9-dihydropyrazino[1',2':1,5]pyrrolo[2,3-d]pyrimidin-7(6H)-yl)prop-2-en-1-one derivatives as novel covalent FGFR2/3 inhibitors through structure-based design and optimization. The lead compound, KNT-0919, potently suppressed FGFR2- or FGFR3-driven Ba/F3 cells (IC50 = 1.1 nM and 0.20 nM), with reduced activity against Ba/F3-FGFR1 cells (IC50 = 17.1 nM) and parental Ba/F3 cells (IC50 > 1000 nM). In a panel of 416 kinases, KNT-0919 selectively inhibited FGFR2/3 kinases, including clinically relevant mutants. Covalent modification of FGFR2/3 was confirmed by mass spectrometry and X-ray crystallography. Functionally, KNT-0919 selectively suppressed the proliferation of FGFR2-dependent cancer cell lines, dose-dependently inhibited FGFR2 downstream signaling, and induced apoptosis in an FGFR2-dependent manner. Moreover, KNT-0919 demonstrated favorable oral bioavailability (56%) in rats and achieved significant tumor growth inhibition in an SNU-16 gastric cancer xenograft model.
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