An inhibitor of Cdks
PHA-848125 is a potent and ATP-competitive Cdk2/cyclin A inhibitor with an IC50 value of 45 nM. PHA-848125 also inhibited Cdk7/cyclin H, Cdk4/cyclin D1, Cdk5/p35, Cdk2/cyclin E and Cdk1/cyclin B with less potency (IC50= 0.15 μM, 0.16 μM, 0.265 μM, 0.363 μM and 0.398 μM, respectively). [1]
CDK (cyclin-dependent kinase) is a group of serine/threonine kinases. It is activated by binding to cyclin and participates in the regulation of cell cycle.
In cells treated with PHA-848125, hyperphosphorylated form of CDK substrate—retinoblastoma protein (pRb) was reduced and hypophosporylated from of pRb was accumulated. It further indicated inhibition effect of PHA-848125 on CDK2 activity. [1]
In human ovarian A2780 xenogaft mouse model, 20, 30 and 40mg/kg of PHA-848125 were each administrated orally twice a day for 10 days. PHA-848125 inhibited A2780 tumor growth up to 91% at 40 mg/kg dose. [1]
Reference:
1. Brasca MG, Amboldi N, Ballinari D et al.? Identification of N,1,4,4-tetramethyl-8-{[4-(4-methylpiperazin-1-yl)phenyl]amino}-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxamide (PHA-848125), a potent, orally available cyclin dependent kinase inhibitor. J Med Chem. 2009 Aug 27;52(16):5152-63.
| Cell experiment [1,2]: | |
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Cell lines |
GL-Mel cells |
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Preparation method |
The solubility of this compound in DMSO is > 23.1 mg/mL. General tips for obtaining a higher concentration: Please warm the tube at 37 ℃ for 10 minutes and/or shake it in the ultrasonic bath for a while. Stock solution can be stored below -20℃ for several months. |
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Reacting condition |
0.156 or 0.625 μM, 72 hours |
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Applications |
Exposure of GL-Mel cells to 0.156 μM PHA-848125 induced a moderate increase in the G1 fraction with no significant changes concerning the S and the G2/M fractions. Treatment with 0.625 μM PHA-848125 caused instead a marked accumulation of the cells in the G1 phase, accompanied by a concomitant strong reduction of the percentage of cells in the S and G2/M phases. PHA-848125 slightly up-regulated the expression of p53 in GL-Mel cells. PHA-848125 showed antiproliferative activity against a panel of 145 tumor cell lines established from different solid tumors and a further 44 cell lines derived from leukemias and lymphomas. |
| Animal experiment [2,3]: | |
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Animal models |
K-Ras(G12D)LA2 mice, human ovarian carcinoma A2780 xenografted mouse model, human xenograft tumors s.c. implanted in athymic mice |
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Dosage form |
Oral administration, 40 mg/kg twice daily for 10 days |
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Application |
In the preclinical xenograft A2780 human ovarian carcinoma model, PHA-848125 showed good efficacy and was well tolerated upon repeated daily treatments. Treatment of K-Ras(G12D)LA2 mice with PHA-848125 (40 mg/kg twice daily for 10 days) resulted in significant tumor growth inhibition at the end of the treatment. PHA-848125 (40 mg/kg orally twice a day × 5 days, repeated for four cycles) significantly increased survival time in two models of human primary disseminated leukemias. |
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Other notes |
Please test the solubility of all compounds indoor, and the actual solubility may slightly differ with the theoretical value. This is caused by an experimental system error and it is normal. |
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参考文献: [1]. Caporali S, Alvino E, Starace G, et al. The cyclin-dependent kinase inhibitor PHA-848125 suppresses the in vitro growth of human melanomas sensitive or resistant to temozolomide, and shows synergistic effects in combination with this triazene compound[J]. Pharmacological research, 2010, 61(5): 437-448. [2]. Albanese C, Alzani R, Amboldi N, et al. Dual targeting of CDK and tropomyosin receptor kinase families by the oral inhibitor PHA-848125, an agent with broad-spectrum antitumor efficacy[J]. Molecular cancer therapeutics, 2010, 9(8): 2243-2254. [3]. Degrassi A, Russo M, Nanni C, et al. Efficacy of PHA-848125, a cyclin-dependent kinase inhibitor, on the K-RasG12DLA2 lung adenocarcinoma transgenic mouse model: evaluation by multimodality imaging[J]. Molecular cancer therapeutics, 2010, 9(3): 673-681. | |
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