生物活性

• 描述Cyclin-dependent kinases (CDKs) are a family of protein kinases which along with their regulatory subunit cyclins play a key role in the growth, development, proliferation and death of eukaryotic cells and are responsible for insuring integrity in the coordination of events through the cell cycle ^[3]. PHA-848125 is a potent, dual inhibitor of CDK and Tropomyosin receptor kinase (TRK), with IC50s of 45, 150, 160, 363, 398 nM and 53 nM for cyclin A/CDK2, cyclin H/CDK7, cyclin D1/CDK4, cyclin E/CDK2, cyclin B/CDK1 and TRKA, respectively ^[4]. 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 ^[4]. PHA-848125 induces a clear accumulation of cells in G1 phase and it strongly inhibits NGF (nerve growth factor)-induced phosphorylation of TRKA (tropomyosin receptor kinase) in a dose-dependent manner ^[5]. PHA-848125 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. PHA-848125 (5, 10, and 15 mg/kg, p.o.) inhibits the growth of tumor in 7, 12-dimethylbenz anthracene (DMBA)-induced rat mammary carcinoma model ^[5].
• 作用机制PHA-848125 is a potent, ATP-competitive CDK inhibitor for CDK2 with IC50 of 45 nM, being > 3-fold selective for CDK2 than CDK1, 2, 4, 5, and 7.
• 细胞研究
• Cell Data

  Cell Lines	Concentration	Assay Type	Time	Activity Description	Data Sources
  human A2780 cells	-	Proliferation assay	72 h	Antiproliferative activity against human A2780 cells after 72 hrs by cell Titer_Glo assay, IC50=0.2 μM	19603809
  human A2780 cells	-	Function assay	-	Inhibition of CDK2 in human A2780 cells assessed as reduction of hyperphosphorylated form of retinoblastoma protein at 1 uM relative to control	19603809

• 临床研究

• NCT号	适应症或疾病	临床期	招募状态	预计完成时间	地点
  NCT03109886	Hepatocellular Carcinoma	Phase 2	Active, not recruiting	August 2019	Greece ... more >> Ippokrateio General Hospital of Athens Athens, Greece, 11527 Laiko General Hospital of Athens Athens, Greece, 11527 General University Hospital of Larissa Larissa, Greece, 41110 University General Hospital of Thessaloniki - AHEPA Thessaloniki, Greece, 54636 Israel Rambam Health Corporation Haifa, Israel, 31096 Rabin Medical Center - Beilinson Hospital Petah Tikva, Israel, 4941492 The Sheba Academic Medical Center Hospital - Tel Hashomer Ramat Gan, Israel Tel Aviv Sourasky Medical Center Tel Aviv, Israel, 64239 Italy Istituto Clinico Humanitas Rozzano, MI, Italy, 20089 AOU S. Orsola Malpighi Bologna Bologna, Italy, 40138 Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico Milano, Italy, 20122 Azienda Ospedaliera Universitaria Policlinico di Modena Modena, Italy, 41124 A.O.U. Federico II Napoli, Italy, 80131 A.O. U. Policlinico Paolo Giaccone Palermo, Italy, 90127 Collapse <<
  NCT01011439	Thymic Carcinoma	Phase 2	Active, not recruiting	December 2018	United States, Arizona ... more >> TGen Clinical Research Services at Scottsdale Healthcare Scottsdale, Arizona, United States, 85258 United States, Maryland NIH, Center for Cancer Research, Medical Oncology Bethesda, Maryland, United States, 20892 France Hopital Larrey Toulouse Cedex, France, 31059 Institut de cancerologie Gustave Roussy Villejuif Cedex, France, 94805 Italy Fondazione IRCCS Istituto Nazionale dei Tumori di Milano Milano, (mi), Italy, 20133 Azienda Ospedaliera San Luigi Gonzaga Orbassano, Italy, 10043 Collapse <<
  NCT01301391	-	-	Active, not recruiting	-	-

• 更多
• 参考文献

• [1] Caporali S, Alvino E, 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. Pharmacol Res. 2010 May;61(5):437-48.

  [2] Brasca MG, Amboldi N, et al. Identification of N,1,4,4-tetramethyl-8-{[4-(4-methylpiperazin-1-yl)phenyl] amino}-4,5-dihydro-1H-py razolo[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.

  [3] Misra RN, Xiao Hy, Rawlins DB, Shan W, Kellar KA, Mulheron JG, Sack JS, Tokarski JS, Kimball SD, Webster KR. 1H-Pyrazolo[3,4-b]pyridine inhibitors of cyclin-dependent kinases: highly potent 2,6-Difluorophenacyl analogues. Bioorg Med Chem Lett. 2003 Jul 21;13(14):2405-8. doi: 10.1016/s0960-894x(03)00381-0. PMID: 12824044.

  [4] Caporali S, Alvino E, Levati L, Esposito AI, Ciomei M, Brasca MG, Del Bufalo D, Desideri M, Bonmassar E, Pfeffer U, D'Atri S. Down-regulation of the PTTG1 proto-oncogene contributes to the melanoma suppressive effects of the cyclin-dependent kinase inhibitor PHA-848125. Biochem Pharmacol. 2012 Sep 1;84(5):598-611. doi: 10.1016/j.bcp.2012.06.004. Epub 2012 Jun 13. PMID: 22704958.

  [5] Albanese C, Alzani R, Amboldi N, Avanzi N, Ballinari D, Brasca MG, Festuccia C, Fiorentini F, Locatelli G, Pastori W, Patton V, Roletto F, Colotta F, Galvani A, Isacchi A, Moll J, Pesenti E, Mercurio C, Ciomei M. Dual targeting of CDK and tropomyosin receptor kinase families by the oral inhibitor PHA-848125, an agent with broad-spectrum antitumor efficacy. Mol Cancer Ther. 2010 Aug;9(8):2243-54. doi: 10.1158/1535-7163.MCT-10-0190. Epub 2010 Aug 3. PMID: 20682657.

• 更多

• Collapse