Milciclib

Milciclib (PHA-848125) is a spectrum selective multi-kinase inhibitor of cyclin-dependent kinases initially identified in a CDK2 inhibitor project, as a potent inhibitor of the CDK2/Cyclin A complex. It possesses an unusual kinase inhibitory profile, being active also against other selected members of receptors tyrosine kinases, src family and splicing kinases.
 
Uncontrolled cell proliferation is a hallmark of cancer cells. Alterations of the expression and/or genetic mutations of Cdks and other components of the pRB pathway, controlling the correct entry and progression through the cell cycle, were reported in more than 90% of human neoplasms.
 
Milciclib is currently in phase II as single agent in thymic carcinoma.

Selected references

  • Phase I study of the oral CDK-TRKA inhibitor PHA-848125 administered with prolonged schedules of administration (American Society of Clinical Oncology Annual Meeting2010,46th:June 7(Abs 3065))
  • Phase I study of the oral CDK-TRKA inhibitor PHA-848125 in combination with gemcitabine in advanced solid tumors (American Society of Clinical Oncology Annual Meeting2010,46th:June 7(Abs 3063))
  • Phase I study of the oral CDK-TRKA inhibitor PHA-848125 in recurrent malignant glioma (MG), (American Society of Clinical Oncology Annual Meeting2010,46th:June 6(Abs 2087))
  • 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
  • Efficacy of PHA-848125, a cyclin-dependent kinase inhibitor, on the K-Ras(G12D)LA2 lung adenocarcinoma transgenic mouse model: evaluation by multimodality imaging, Mol Cancer Ther. 2010 Mar;9(3):673-81
  • 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
  • Phase II Study Of Oral PHA-848125AC In Patients With Thymic Carcinoma Previously Treated With Chemotherapy, NCT01011439, www.clinicaltrial.gov
  • 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
  • Gateways to clinical trials, Methods Find Exp Clin Pharmacol. 2009 Apr;31(3):183-226
  • A phase I dose-escalation study of danusertib (PHA-739358) administered as a 24-hour infusion with and without granulocyte colony-stimulating factor in a 14-day cycle in patients with advanced solid tumors, Clin Cancer Res. 2009 Nov 1;15(21):6694-701
  • Phase I dose escalation study of the oral multi-CDK inhibitor PHA-848125 (American Society of Clinical Oncology Annual Meeting2008,44th:May 31(Abs 3531))