Discovery of acyl ureas as highly selective small molecule CSF1R kinase inhibitors
Timothy M. Caldwell, Michael D. Kaufman, Scott Wise, Yu Mi Ahn, Molly M. Hood, Wei-Ping Lu, William C. Patt, Thiwanka B. Samarakoon, Lakshminarayana Vogeti, Subha Vogeti, Karen M. Yates, Stacie L. Bulfer, Bertrand Le Bourdonnec, Bryan D. Smith, Daniel L. Flynn
Abstract
Based on the structure of an early lead identified in Deciphera's proprietary compound collection of switch control kinase inhibitors and using a combination of medicinal chemistry guided structure activity relationships and structure-based drug design, a novel series of potent acyl urea-based CSF1R inhibitors was identified displaying high selectivity for CSF1R versus the other members of the Type III receptor tyrosine kinase (RTK) family members (KIT, PDGFR-α, PDGFR-β, and FLT3), VEGFR2 and MET. Based on in vitro biology, in vitro ADME and in vivo PK/PD studies, compound 10 was selected as an advanced lead for Deciphera's CSF1R research program.