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: dflynn@deciphera.com.

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/KDR/Flk-1 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.

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