KY-065

**KY-065** is a potent, selective, and ATP-competitive small molecule inhibitor of cyclin-dependent kinase 8 (CDK8) and CDK19, with IC50 values of 4.4 nM and 3.6 nM, respectively, with minimal cross-reactivity against other CDK family kinases[5][2][1]. It inhibits CDK8 primarily by competing at the ATP binding site and preferentially binds to the DMG-out conformation of the kinase[3]. Mechanistically, KY-065 suppresses CDK8-mediated phosphorylation of STAT1 at Ser727 in chondrocytes, reducing abnormal downstream signaling associated with conditions such as achondroplasia (ACH) and osteoporosis[2][3][1]. Preclinical studies show that KY-065 restores normal chondrogenic differentiation and promotes elongation of long bones in a mouse model of achondroplasia, as well as preventing bone loss in a postmenopausal osteoporosis mouse model, primarily by modulating mesenchymal stem cells and their signaling to osteoclasts[2][1]. KY-065 was internally developed and is being studied primarily in academic and preclinical research settings as a promising therapeutic for ACH and osteoporosis, with ongoing research to determine potential utility in human disease[2][3][1].

Other names

4-acetyl-3-{4-[2-(tetrahydropyran-4-yloxy)ethoxy]phenoxy}benzamide