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).

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.

• Authors: Timothy M Caldwell, Yu Mi Ahn, Stacie L Bulfer, Cynthia B Leary, Molly M Hood, Wei-Ping Lu, Lakshminarayana Vogeti, Subha Vogeti, Michael D Kaufman, Scott C Wise, Bertrand Le Bourdonnec, Bryan D Smith, Daniel L Flynn
• Journal: Bioorganic & medicinal chemistry letters (Bioorg Med Chem Lett) Vol. 74 Pg. 128928 (10 15 2022) ISSN: 1464-3405 [Electronic] England
• PMID: 35961460 (Publication Type: Journal Article)
• Copyright: Copyright © 2022. Published by Elsevier Ltd.

Chemical References

• Antineoplastic Agents
• DCC Receptor
• DCC protein, human
• Protein Kinase Inhibitors
• Receptor Protein-Tyrosine Kinases
• Receptor, Macrophage Colony-Stimulating Factor

Topics

• Antineoplastic Agents (pharmacology, therapeutic use)
• DCC Receptor
• Giant Cell Tumor of Tendon Sheath (drug therapy, pathology)
• Humans
• Protein Kinase Inhibitors (pharmacology, therapeutic use)
• Receptor Protein-Tyrosine Kinases
• Receptor, Macrophage Colony-Stimulating Factor