PHA-848125

本公司产品仅用于科研实验，不得用于人体或动物的临床与诊断

一种有效、选择性、脑渗透性、口服的双重 CDK 和 TRK 抑制剂，对 CDK2/cyclin A 和 TrkA 的 IC50 分别为 45 和 53 nM；显示与其他 CDK (CDK1/4/5/7)、TrkB/C、Kit、Abl 和 PDGFR 的交叉反应性 (IC50<1 uM)。

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.

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.

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.

Milciclib | PHA 848125

Cell Cycle/DNA Damage

CDK

CDK2/CyclinA| CDK4/CyclinD1| CDK5/p35| CDK7/CyclinH| TrkA

Cancer

Brain Cancer

802539-81-7

460.5746

C25H32N8O

>98% (HPLC)

10 mM in DMSO

O=C(C1=NN(C)C2=C1C(C)(C)CC3=CN=C(NC4=CC=C(N5CCN(C)CC5)C=C4)N=C23)NC

1H-Pyrazolo[4,3-h]quinazoline-3-carboxamide, 4,5-dihydro-N,1,4,4-tetramethyl-8-[[4-(4-methyl-1-piperazinyl)phenyl]amino]-

(-20℃)

With Ice Pack

≥ 2 years