期刊
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
卷 74, 期 -, 页码 -出版社
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bmcl.2022.128928
关键词
Kinase; CSF1R; Switch -control; Cancer; TGCT
Based on knowledge of kinase switch-control inhibition, a novel series of dihydropyrimidone-based CSF1R kinase inhibitors were identified using structure-based drug design and standard medicinal chemistry principles. These inhibitors displayed high selectivity for CSF1R over a wide range of kinases and non-kinase protein targets. Compound 20 (vimseltinib) emerged as a lead candidate for clinical evaluation in the treatment of Tenosynovial Giant Cell Tumor (TGCT).
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 (DCC3014; 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.
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