Inhibitors of cyclin-dependent kinase modulators for cancer therapy.
Most human malignancies have an aberration in the Rb pathway due to 'cdk hyperactivation'. Several small-molecule cdk modulators are being discovered and tested in the clinic. The first ATP-competitive cdk inhibitors tested in clinical trials, flavopiridol and UCN-01, have shown promising results with evidence of antitumor activity and plasma concentrations sufficient to inhibit cdk-related functions. The best schedule to be administered, combination with standard chemotherapeutic agents, best tumor types to be targeted, and demonstration of cdk modulation from tumor samples from patients in these trials are important issues that need to be answered to advance these agents to the clinical arena.
Senderowicz
Adrian M
AM
Radiation Biology Branch, National Cancer Institute, National Institutes of Health, Bldg. 10, Room B3-B6, Bethesda, MD 20892, USA. sendero@helix.nih.gov
D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D002453:Cell Cycle; D002986:Clinical Trials as Topic; D018844:Cyclin-Dependent Kinases / Q000037:antagonists & inhibitors*; D005419:Flavonoids / Q000627:therapeutic use; D006801:Humans; D009369:Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D010880:Piperidines / Q000627:therapeutic use; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use*; D019311:Staurosporine / Q000031:analogs & derivatives / Q000627:therapeutic use
D000970:Antineoplastic Agents; D005419:Flavonoids; D010880:Piperidines; D047428:Protein Kinase Inhibitors; C077990:alvocidib; C054852:7-hydroxystaurosporine; D018844:Cyclin-Dependent Kinases; D019311:Staurosporine