Discovery of vimseltinib (DCC-3014), a highly selective CSF1R switch-control kinase inhibitor, in clinical development for the treatment of Tenosynovial Giant Cell Tumor (TGCT)

  • Bioorg Med Chem Lett. 2022 Oct 15:74:128928. doi: 10.1016/j.bmcl.2022.128928.
Timothy M Caldwell  1 ,  Yu Mi Ahn  1 ,  Stacie L Bulfer  1 ,  Cynthia B Leary  1 ,  Molly M Hood  1 ,  Wei-Ping Lu  1 ,  Lakshminarayana Vogeti  1 ,  Subha Vogeti  1 ,  Michael D Kaufman  1 ,  Scott C Wise  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: 35961460 DOI: 10.1016/j.bmcl.2022.128928
Abstract

Based on knowledge of kinase switch-control inhibition and using a combination of structure-based drug design and standard medicinal chemistry principles, we identified a novel series of dihydropyrimidone-based CSF1R kinase inhibitors displaying exquisite selectivity for CSF1R versus a large panel of kinases and non-kinase protein targets. Starting with lead compound 3, an SAR optimization campaign led to the discovery of vimseltinib (DCC-3014; compound 20) currently undergoing clinical evaluation for the treatment of Tenosynovial Giant Cell Tumor (TGCT), a locally aggressive benign tumor associated with substantial morbidity. 2021 Elsevier ltd. All rights reserved.

Keywords
CSF1R; Cancer; Kinase; Switch-control; TGCT.