Discovery of 4-((N-(2-(dimethylamino)ethyl)acrylamido)methyl)-N-(4-methyl-3-((4-(pyridin-3-yl)pyrimidin-2-yl)amino)phenyl)benzamide (CHMFL-PDGFR-159) as a highly selective type II PDGFRα kinase inhibitor for PDGFRα driving chronic eosinophilic leukemia

Through exploration of the non-highly conserved allosteric hydrophobic pocket generated by DFG-out shifting in the inactive conformation, we discovered a highly selective type II PDGFR alpha kinase inhibitor 15i (CHMFL-PDGFR alpha-159), which exhibited strong potency against purified PDGFR alpha (IC50: 132 nM) but not structurally similar PDGFR beta, ABL, c-KIT and VEGFR2 kinases. In addition, it displayed a high selectivity profile (S score (10) = 0.02) at the concentration of 1 mu M among 468 kinases/mutants in the KINOMEscan profiling. X-ray crystal structure of 15i in complex with PDGFR? revealed a distinct binding feature in the allosteric hydrophobic pocket which might help to expand the diversity of type II kinase inhibitors. Compound 15i potently inhibited the proliferation of PDGFR alpha driving Chronic Eosinophilic Leukemia (CEL) cell line EOL-1 through strong blockage of PDGFR alpha mediated signaling pathways, arresting cell cycle progression, and induction of apoptosis. Furthermore, compound 15i effectively suppressed the EOL-1 tumor progression in the xenograft model and increased the survival rate in the engraftment tumor model. (C) 2018 Elsevier Masson SAS. All rights reserved.