Cyclin-dependent kinase inhibitors
Flavopiridol, roscovitine (CYC202, seliciclib) and SNS-032 are selective inhibitors of cyclin-dependent kinases (Cdks) 7 and 9. These Cdks phosphorylate critical serine residues in the carboxy-terminal domain of RNA polymerase II, thereby enabling this enzyme to initiate and elongate RNA transcripts. The rationale for these agents in cancer treatment is that short-lived anti-apoptotic proteins are depleted more rapidly in response to transcription inhibition than long-lived proteins following Cdk inhibition. Flavopiridol, roscovitine and SNS-032 inhibit C-terminal phosphorylation of RNA polymerase II, decrease cellular levels of the anti-apoptotic proteins Mcl-1 and XIAP and induce apoptosis of CLL cells in vitro.
Flavopiridol killed CLL cells in vitro regardless of previous treatment history. Killing was independent of the expression of anti-apoptotic Bcl-2 relative to pro-apoptotic Bax, whereas the toxicity of fludarabine was strongly dependent on this ratio. Flavopiridol induced partial remissions (40%) with a median progression-free survival duration of 12 months, even in patients refractory to fludarabine or with poor-risk genetic features (i.e. deletion of TP53 or ATM genes). A Phase II trial confirmed the conclusions of the Phase I study and indicated that the dosing schedule was critical. Prophylactic dexamethasone might improve tolerability by reducing the risk of the cytokine release syndrome.
Roscovitine induced apoptosis of CLL cells and downregulation of pro-survival proteins including Mcl-1, probably by inhibition of RNA polymerase phosphorylation and is in clinical trials for solid tumours.
Limited clinical activity of SNS-032 was seen in a Phase I clinical trial of SNS-032, with tumour lysis syndrome as the dose-limiting toxicity. Further modification of drug doses and scheduling are likely to be required to maximize the clinical efficacy of this agent and of other CDK inhibitors.