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)

作者：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 Wise, Bertrand Le Bourdonnec, Bryan D. Smith, Daniel L. Flynn · 发表于：Bioorganic & Medicinal Chemistry Letters · 年份：2022 · DOI：10.1016/j.bmcl.2022.128928 · 被引用次数：42 · 研究领域：Multiple Myeloma Research and Treatments、Quinazolinone synthesis and applications、Musculoskeletal synovial abnormalities and treatments

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.