PHA-793887

PHA-793887 is a potent, ATP-competitive CDK inhibitor, can inhibit Cdk2, Cdk1, Cdk4, and Cdk9 with IC₅₀s of 8 nM, 60 nM, 62 nM and 138 nM, respectively, and also inhibits glycogen synthase kinase 3β with an IC₅₀ of 79 nM. IC50 & Target: IC50: 8 nM (Cdk2), 60 nM (Cdk1), 62 nM (Cdk4) 138 nM (Cdk9), 79 nM (GSK-3β)^[1][4], 5 nM (CDK5/p25), 10 nM (CDK7/cyclin H)^[4]
Ki: 8 nM (CDK2/Cyclin A)^[2] In Vitro: PHA-793887 partially inhibits Rb phosphorylation at 1 μM and almost completely at 3 μM, in A2780 tumor cell line. PHA-793887 (1 μM) partially inhibits phosphorylation of the Cdk2 substrates Rb and NPM in A2780 tumor cell line. PHA-793887 (6 μM) significantly inhibits Rb and NPM phosphorylation in MCF7 cell line^[1]. PHA-793887 shows cytotoxic activities against leukemic cell lines in vitro, with IC₅₀ ranging from 0.3 to 7 μM. In colony assays, PHA-793887 is highly cytotoxic for leukemia cell lines, with an IC₅₀ <0.1 μM. PHA-793887 induces cell-cycle arrest, inhibits Rb and nucleophosmin phosphorylation, and modulates cyclin E and cdc6 expression at low doses of 0.2 to 1 μM and induces apoptosis at the highest dose of 5 μM. PHA-793887 is a novel inhibitor of several cdk, including cdk1, cdk2, cdk4, cdk5, cdk7, and cdk9 with IC₅₀ in the 5 to 140 nM range^[3]. In Vivo: PHA-793887 induces tumor growth inhibition in the range of 50% at dose of 15 mg/kg to 75% at dose of 30 mg/kg in CD-1 nude mice. PHA-793887 (30 mg/kg, i.v.) also induces significant downregulation of the 58-gene panel in the skin of CD-1 mice^[1]. PHA-793887 (20 mg/kg, i.v.) induces tumor regression in the HL60 model. In the K562 model, PHA-793887 significantly reduces tumor growth. Moreover, PHA-793887 (20 mg/kg, i.v.) inhibits human primary leukemia growth in engraftment setting in vivo^[3].