AT-7519 hydrochloride

A potent CDK2 inhibitor with IC50 of 47 nM; also inhibits CDK1/4/5 with IC50 of 190/67/18 nM and shows selectivity over some kinases (Aurora A, IR kinase, MEK, PDK1, c-Abl, IC50>10 uM) ; has antiproliferative activity against HCT116 cells with IC50 of 82 nM; exhibits good profile against cytochrome P450 isoforms (<30% inhibition at 10 uM for 1A2, 2D6, 3A4, 2C9, 2C19) .Blood Cancer Phase 2 Clinical (In Vitro) :AT7519 (0-4 μM) results in dose-dependent cytotoxicity with IC50s ranging from 0.5 to 2 μM in MM cells, and this induced cytotoxicity is associated with GSK-3β activation independent of transcriptional inhibition. AT7519 overcomes proliferative advantage conferred by cytokines and the protective effect of BMSC. AT7519 (0.5 μM) induces apoptosis of MM cells in a time-dependent manner. Moreover, AT7519 (0.5 μM) inhibits phosphorylation of RNA polymerase II CTD and partially inhibits RNA synthesis in MM.1S cells. AT7519 (250 nM) inhibits cell cycle progression in human tumor cell lines. AT7519 also induces apoptosis of human tumor cell lines. AT7519 (100-700 nM) induces apoptosis in leukemia cell lines. AT7519 also inhibits transcription in human tumor cell lines. Furthermore, AT7519 inhibits RNA polymerase II and reduces antiapoptotic protein levels. (In Vivo) :AT7519 inhibits tumor growth in a human MM xenograft mouse model. AT7519 (4.6 and 9.1 mg/kg/dose) inhibits the growth of early-stage HCT116 tumor xenografts. AT7519 (10 mg/kg, i.p.) also inhibits the target CDKs in HCT116 tumor-bearing BALB/c nude mice.