Recent progress in the discovery and development of cyclin-dependent kinase inhibitors.
Cyclin-dependent kinases (CDKs) have long been known to be the main facilitators of the cell proliferation cycle. However, they also play important roles in the regulation of the RNA polymerase II transcription cycle. Cancer cells display aberrant cell cycle regulation to gain proliferative advantages and they also appear to have an exaggerated dependence on RNA polymerase II transcriptional activity to sustain pro-survival and antiapoptotic signalling. A picture is now starting to emerge that both the cell-cycle and transcriptional functions of CDKs can be exploited pharmacologically with CDK inhibitors that possess appropriate selectivity profiles. In this article, recent advances into these mechanistic insights and how they can guide clinical development in terms of choice of indication are reviewed, as well as combinations with existing chemotherapies. An overview is also given of recent clinical trial results with the lead CDK inhibitor drug candidates seliciclib (CYC202, (R)-roscovitine; Cyclacel) and alvocidib (flavopiridol; Aventis-NCI), as well as the development of other clinical entries and advanced preclinical compounds. The discussion focuses on oncology, but we point out recent results with CDK inhibitors in virology and nephrology.
Fischer
Peter M
PM
Cyclacel Limited, James Lindsay Place, Dundee DD1 5JJ, Scotland, UK. pfischer@cyclacel.com
Gianella-Borradori
Athos
A
D000595:Amino Acid Sequence; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D002986:Clinical Trials as Topic; D018844:Cyclin-Dependent Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D019008:Drug Resistance, Neoplasm; D005260:Female; D005419:Flavonoids / Q000494:pharmacology / Q000627:therapeutic use; D005921:Glomerulonephritis / Q000188:drug therapy / Q000201:enzymology; D015658:HIV Infections / Q000188:drug therapy / Q000201:enzymology; D019337:Hematologic Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D006801:Humans; D008969:Molecular Sequence Data; D010880:Piperidines / Q000494:pharmacology / Q000627:therapeutic use; D047428:Protein Kinase Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D011687:Purines / Q000494:pharmacology / Q000627:therapeutic use; D000077546:Roscovitine; D014158:Transcription, Genetic / Q000187:drug effects
D000970:Antineoplastic Agents; D005419:Flavonoids; D010880:Piperidines; D047428:Protein Kinase Inhibitors; D011687:Purines; D000077546:Roscovitine; C077990:alvocidib; D018844:Cyclin-Dependent Kinases