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: dflynn@deciphera.com.

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.

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