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Milciclib

Description of Milciclib (PHA-848125): Milciclib is an orally bioavailable inhibitor of cyclin-dependent kinases (CDKs) and thropomyosin receptor kinase A (TRKA), with potential antineoplastic activity. CDK2/TRKA inhibitor PHA-848125 AC potently inhibits cyclin-dependent kinase 2 (CDK2) and exhibits activity against other CDKs including CDK1 and CDK4, in addition to TRKA. Inhibition of these kinases may result in cell cycle arrest and apoptosis of tumor cells that express these kinases. CDKs are serine/threonine kinases involved in regulation of the cell cycle and may be overexpressed in some cancer cell types. The neurotrophin receptor TRKA is mutated in a variety of cancer cell types. Check for active clinical trials or closed clinical trials using this agent. (NCI Thesaurus) .

Current developer:    Nerviano Medical Sciences

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. (source: http://www.nervianoms.com/en/oncology-en/pipeline/milciclib.html).

1: Degrassi A, Russo M, Nanni C, Patton V, Alzani R, Giusti AM, Fanti S, Ciomei M, Pesenti E, Texido G. 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. Epub 2010 Mar 2. PubMed PMID: 20197397.

2: Caporali S, Alvino E, Starace G, Ciomei M, Brasca MG, Levati L, Garbin A, Castiglia D, Covaciu C, Bonmassar E, D'Atri S. 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. Epub 2009 Dec 21. PubMed PMID: 20026273.

3: Brasca MG, Amboldi N, Ballinari D, Cameron A, Casale E, Cervi G, Colombo M, Colotta F, Croci V, D'Alessio R, Fiorentini F, Isacchi A, Mercurio C, Moretti W, Panzeri A, Pastori W, Pevarello P, Quartieri F, Roletto F, Traquandi G, Vianello P, Vulpetti A, Ciomei M. 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 Jul 15. [Epub ahead of print] PubMed PMID: 19603809.

4: Tomillero A, Moral MA. Gateways to clinical trials. Methods Find Exp Clin Pharmacol. 2009 Apr;31(3):183-226. PubMed PMID: 19536362.