PHA-848125

A potent, selective, brain penetrant and orally available dual CDK and TRK inhibitor with IC50 of 45 and 53 nM for CDK2/cyclin A and TrkA, respectively; shows cross-reactivity with other CDKs (CDK1/4/5/7), TrkB/C, Kit, Abl and PDGFR (IC50s<1 uM) ; nhibits cell proliferation of a wide panel of tumoral cell lines with submicromolar IC50; shows significant antitumor activity in various human xenografts.Brain Cancer Phase 2 Clinical (In Vitro) :Milciclib (PHA-848125; 0.156 or 0.625 μM) up-regulates the expression of PDCD4, DDIT4, SESN2/sestrin 2 and DEPDC6/DEPTOR in GL-Mel cells. Milciclib (PHA-848125) potently inhibits the kinase activity of CDK2/cyclin A complex and of TRKA in a biochemical assay, with IC50s of 45 and 53 nM, respectively. Milciclib induces a clear accumulation of cells in G1 phase. Milciclib strongly inhibits NGF-induced phosphorylation of TRKA in a dose-dependent manner. (In Vivo) :Milciclib (PHA-848125; 5, 10, and 15 mg/kg, p.o.) inhibits the growth of tumor in 7,12-dimethylbenz (a) anthracene (DMBA) -induced rat mammary carcinoma model. Milciclib has significant antitumor activity in various human xenografts and carcinogen-induced tumors as well as in disseminated primary leukemia models, with plasma concentrations in rodents in the same range as those found active in inhibiting cancer cell proliferation. Milciclib (PHA-848125; 40 mg/kg) induces a significant tumor growth inhibition in K-RasG12DLA2 mice, and this is accompanied by a reduction in the cell membrane turnover.