Drugging cell cycle kinases in cancer therapy.
Cell cycle kinases are comprised of cyclin-dependent kinases (Cdks), non-Cdk kinases such as Plk-1 and Aurora and checkpoint proteins such as Chk1 and Chk2. Though ubiquitous to dividing cells, many cell cycle kinases are amplified or over-expressed in malignancy and are potential targets for anti-cancer therapies. Cdk inhibiting drugs (such as flavopiridol, UCN-01, E7070, R-Roscovitine and BMS-387032) have shown preclinical and clinical anticancer activity. However, many of these agents are promiscuous and undiscerning, targeting other non-cell cycle kinases and affecting normal cells, thereby causing significant toxicity. To overcome this, a new generation of Cdk inhibitors are in development with greater target specificity, as well as others that inhibit non-Cdk cell cycle kinases, both directly and indirectly. The outcome of early clinical trials involving these agents is awaited, but these certainly represent a promising new area of anticancer drug development.
Blagden
S
S
Centre for Cancer Therapeutics, Institute for Cancer Research, Royal Marsden Hospital, Downs Road, Sutton, Surrey SM2 5PT, England. jdebono@icr.ac.uk
de Bono
J
J
D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D001665:Binding Sites; D018844:Cyclin-Dependent Kinases / Q000037:antagonists & inhibitors* / Q000502:physiology; D005419:Flavonoids / Q000627:therapeutic use; D006801:Humans; D009369:Neoplasms / Q000188:drug therapy*; D010080:Oxazoles / Q000627:therapeutic use; D010880:Piperidines / Q000627:therapeutic use; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use*; D011687:Purines / Q000627:therapeutic use; D000077546:Roscovitine; D019311:Staurosporine / Q000031:analogs & derivatives* / Q000627:therapeutic use; D013449:Sulfonamides / Q000627:therapeutic use; D013844:Thiazoles / Q000627:therapeutic use
D000970:Antineoplastic Agents; D005419:Flavonoids; C439829:N-(3-chloro-7-indolyl)-1,4-benzenedisulphonamide; C484864:N-(5-(((5-(1,1-dimethylethyl)-2-oxazolyl)methyl)thio)-2-thiazolyl)-4-piperidinecarboxamide; D010080:Oxazoles; D010880:Piperidines; D047428:Protein Kinase Inhibitors; D011687:Purines; D013449:Sulfonamides; D013844:Thiazoles; D000077546:Roscovitine; C077990:alvocidib; C054852:7-hydroxystaurosporine; D000255:Adenosine Triphosphate; D018844:Cyclin-Dependent Kinases; D019311:Staurosporine