Discovery of acyl ureas as highly selective small molecule CSF1R kinase inhibitors

  • Bioorg Med Chem Lett. 2022 Oct 15:74:128929. doi: 10.1016/j.bmcl.2022.128929.
Timothy M Caldwell  1 ,  Michael D Kaufman  1 ,  Scott C Wise  1 ,  Yu Mi Ahn  1 ,  Molly M Hood  1 ,  Wei-Ping Lu  1 ,  William C Patt  1 ,  Thiwanka Samarakoon  1 ,  Lakshminarayana Vogeti  1 ,  Subha Vogeti  1 ,  Karen M Yates  1 ,  Stacie L Bulfer  1 ,  Bertrand Le Bourdonnec  1 ,  Bryan D Smith  1 ,  Daniel L Flynn  2
Affiliations
  • 1. Deciphera Pharmaceuticals, LLC, Waltham, MA 02451, United States.
  • 2. Deciphera Pharmaceuticals, LLC, Waltham, MA 02451, United States. Electronic address: [email protected].
PMID: 35961461 DOI: 10.1016/j.bmcl.2022.128929
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.

Keywords
Acyl ureas; CSF1R; Cancer; Kinase.