Seliciclib (CYC202, R-roscovitine) is a tri-substituted purine inhibitor of CDKs 2, 7 and 9 that is currently in Phase II clinical development in patients with advanced NSCLC and Nasopharyngeal Cancer. In vivo seliciclib is rapidly metabolised to an inactive carboxylate. A project was initiated to identify derivatives of seliciclib that had a different metabolic profile and improved potency. A series of tri-substituted purines were synthesised and screened in kinase assays to confirm that they had a similar CDK inhibitor profile. The more potent compounds were then analysed in a screening cascade to demonstrate that they had a similar cellular mode-of-action profile to seliciclib. This included evaluation of the compound effects on 1) cell cycle profile; 2) gene expression changes and 3) phosphorylation status of known CDK substrates. All the compounds analysed behaved very similarly to seliciclib but with up to a 40-fold improvement in cellular potency. Four compounds were selected for more in-depth studies including in vitro ADME & specificity assays, and in vivo pharmacokinetic & xenograft models. Compared to seliciclib significantly improved efficacy has been obtained with once a day oral dosing. Based on the superior pharmaceutical properties and in vivo efficacy one molecule was selected for further development. Results from these ongoing studies will be presented.

Citation Information: In: Proc Am Assoc Cancer Res; 2009 Apr 18-22; Denver, CO. Philadelphia (PA): AACR; 2009. Abstract nr 3863.

100th AACR Annual Meeting-- Apr 18-22, 2009; Denver, CO