CH6953755

CH6953755 is a potent, selective, and orally active small molecule inhibitor of the YES1 kinase, a member of the SRC family of tyrosine kinases. Developed by Chugai Pharmaceutical, it targets YES1 with an IC50 of 1.8 nM. The compound demonstrates significant antitumor activity in cancers characterized by YES1 gene amplification, such as esophageal squamous cell carcinoma and small cell lung cancer (SCLC). Mechanistically, CH6953755 inhibits YES1 kinase activity, which in turn regulates YAP1 transcriptional activity by controlling its nuclear translocation and serine phosphorylation. Preclinical studies have shown that CH6953755 can induce tumor regressions in xenograft models and may also overcome resistance to PARP inhibitors in BRCA1-deficient epithelial ovarian cancer by blocking the YES1-mediated phosphorylation and mitochondrial translocation of EZH2.