Vimseltinib (DCC-3014) is an oral switch-control tyrosine kinase inhibitor specifically designed to selectively and potently inhibit colony-stimulating factor 1 receptor (CSF1R) kinase. Vimseltinib exhibits greater than 500-fold selectivity from the homologous type III receptor tyrosine kinase (RTK) KIT and &gt;1,000-fold selectivity against 300 other human kinases including other type III RTKs PDGFRa/b and FLT3. We will describe the structure and discovery of vimseltinib, which utilized structure-based drug design and structure-activity relationships (SAR) to optimize overall drug properties. Vimseltinib substantially inhibited CSF1R in a murine PK/PD model at doses as low as 3 mg/kg. In an MC38 colorectal syngeneic cancer model, vimseltinib (10 mg/kg daily) depleted immunosuppressive tumor-associated macrophages (TAMs), repolarized the adaptive immune cell population to an anti-tumoral profile, and depleted circulating CD16+ monocyte populations. Vimseltinib in combination with a murine anti-PD1 antibody demonstrated additive antitumor effects compared to single agent cohorts. Additionally, vimseltinib exhibited anti-osteolytic activity in a mouse prostate cancer bone invasion model. Vimseltinib exhibited optimized biopharmaceutical properties, including a favorable ADME and PK profile in preclinical studies.<br/>Tenosynovial giant cell tumor (TGCT) is a rare, locally aggressive neoplasm caused by translocation of the <i>CSF1</i> gene leading to overexpression of CSF1 (the CSF1R ligand), resulting in recruitment/proliferation of macrophages and other CSF1-dependent inflammatory cells. Vimseltinib is currently being evaluated in Phase 1/2 clinical studies for the treatment of TGCT and other solid tumors (NCT03069469; NCT04242238). Initial pharmacodynamic and efficacy data in TGCT patients will be presented.

Discovery of vimseltinib (DCC-3014), a highly selective switch-control inhibitor of CSF1R kinase

ACS Spring Meeting 2021

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