PHA-767491 (hydrochloride)

PHA-767491 hydrochloride is a dual Cdc7/Cdk9 inhibitor, with IC₅₀s of 10 nM and 34 nM, respectively. IC50 & Target: IC50: 10 nM (Cdc7), 34 nM (Cdk9)^[1][4], 240 nM (Cdk2), 250 nM (Cdk1), 460 nM (Cdk5), 220 nM (GSK3-β)^[4] In Vitro: PHA-767491 inhibits proliferation in both cell lines with an IC₅₀ of 0.64 µM in HCC1954 cells and 1.3 µM in Colo-205 cells. PHA-767491 is effective DDK inhibitors in vitro, with IC₅₀ values of 18.6 nM. PHA-767491 (2 µM) completely abolishes Mcm2 phosphorylation by 24 hours in HCC1954 cells^[1]. PHA-767491 in combination with 5-FU exhibits much stronger cytotoxicity and induces significant apoptosis manifested by remarkably increased caspase 3 activation and poly(ADP-Ribose) polymerase fragmentation in HCC cells. PHA-767491 directly counteracts the 5-FU-induced phosphorylation of Chk1 and decreases the expression of the anti-apoptotic protein myeloid leukemia cell 1ine^[2]. PHA-767491 (0-10 µM) decreases glioblastoma cell viability in a time- and dose-dependent fashion, with IC₅₀ of approximately 2.5 µM for U87-MG and U251-MG cells. PHA-767491 hydrochloride induces apoptosis in glioblastoma cells, suppresses glioblastoma cell proliferation, cell migration and cell invasion^[3]. In Vivo: PHA-767491 decreases Chk1 phosphorylation and increases in situ cell apoptosis in tumor tissues sectioned from nude mice HCC xenografts^[2].