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)

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.

Automated summary

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).