PHA-848125

PHA-848125 is a potent ATP-competitive cyclin A/CDK2 inhibitor with an IC50 of 45 nM. HA-848125 inhibits, although with lower potency, the activities of cyclin H/CDK7, cyclin D1/CDK4, p35/CDK5, as well as cyclin E/CDK2 and cyclin B/CDK1 with IC50 of 0.15, 0.16, 0.265, 0.363, 0.398 μM, respectively.Besides, thropomyosin receptor kinase A is also prevented by PHA-848125 in the same nanomolar range of CDKs. In the most PHA-848125-sensitive cell line, PHA-848125 induces a concentration-dependent G (1) arrest.PHA-848125 also impairs phosphorylation of the retinoblastoma protein at CDK2 and CDK4 specific sites, reduces retinoblastoma protein and cyclin A levels, and increases p21 (Cip1), p27 (Kip1) and p53 expression. PHA-848125 is added to the cells 48 hours after TMZ and cell growth is evaluated after 3 additional days of culture.Drug combination of TMZ, BG and PHA-848125 produces additive or synergistic effects on cell growth, depending on the cell line. When TMZ plus BG are used in combination with PHA-848125 against cultured normal melanocytes, neither synergistic nor additive antiproliferative effects are observed.In the preclinical xenograft A2780 human ovarian carcinoma model PHA-848125 reveals good efficacy and is well tolerated upon repeated daily treatments. Treatment of K-Ras (G12D)LA2 mice with 40 mg/kg twice daily for 10 days with PHA-848125 blocks the growth of a significant tumor at the end of treatment and is accompanied by a reduction in the cell membrane turnover. On the other hand, PHA-848125 posseseese significant antitumor activity in various human xenografts, carcinogen-induced tumors and in disseminated primary leukemia models.