PHA-848125

SKU: orb1941014

Description

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.\n(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.

Key Properties

• CAS Number: 802539-81-7
• MW: 460.5746
• Purity: >98% (HPLC)
• Formula: C₂₅H₃₂N₈O
• SMILES: O=C(C1=NN(C)C2=C1C(C)(C)CC3=CN=C(NC4=CC=C(N5CCN(C)CC5)C=C4)N=C23)NC
• Target: CDK
• Solubility: 10 mM in DMSO

Bioactivity

• 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.
• 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.

Storage & Handling

• Storage: Storage temperature: -20°C. Stability: ≥ 2 years
• Expiration Date: 12 months from date of receipt.
• Disclaimer: For research use only

Alternative Names

Milciclib | PHA 848125

Quick Database Links

Gene Symbol

CDK