Design, Synthesis And Antitumor Activity Evaluation Of Plk1 Inhibitors

Polo-like kinases belong to a large family of serine/threonine kinases across eukaryotic species. As a key regulator of multiple steps during cell-cycle progression and cytokinesis, Plkl is over-expressed in 80% human tumor cells such us breast cancer, colorectal cancer, prostate cancer, pancreatic cancer, non-small cell lung cancer, ovarian cancer, while rarely expressed in normal tissues. Specific inhibition of Plkl activity benefits to the treatment of cancer, therefore it has become an attractive target for the development of anti-cancer drugs. Currently some Plk1 inhibitors are under evaluation in clinical trials. Because of the poor selectivity and pharmacokinetics, it is critical to develop orally available selective Plkl inhibitors.BI 2536 is the first Plkl inhibitor in clinical trial. In this study, by employing techniques of structure-based drug design, the structure of BI 2536 was modified with the aim to increase the poentcy and selectivity. Many compounds were synthesized for structure-activity relationship study and comfirmed by NMR and MS. They were assayed for their inhibitions against Plk family and several cancer cell lines.The data suggested that most of the compounds had low nanomolar activity against Plkl as well as high selectivity against Plk2 and Plk3. Among them, the best compound is C2 with an ICso value of 4.134 nM against Plkl, better than BI 2536 and staurosporine. The selectivity profile versus Plk2-3 increased more than 54-fold and 35-fold, respectively. In addition, compound C2 displayed better antiproliferative activities with IC50 value of 40.69 nM,41.67 nM and 37.71 nM against cancer cell lines of MCF-7, K562 and Hela.This study provides potential drug candidates for developing anti-cancer drugs by targeting the Plkl.