Identification of GSK461364, a novel small molecule polo-like kinase 1 inhibitor for the treatment of cancer

4171 Polo-like kinase 1 (Plk1) plays an important role in the entry to, progression through, and exit from mitosis. The multiple roles Plk1 plays in mitosis make it an intriguing target to inhibit to disrupt the cell cycle and treat cancer. This presentation will highlight the lead optimization studies and elucidation of the structure-activity relationship leading to the identification of a novel thiophene amide Plk1 inhibitor. It will include the synthesis of a Plk-selective inhibitor, in addition to optimization of potency and developability characteristics through several iterations of structural changes, culminating in the identification of the clinical candidate. These efforts led to the development of GSK461364, an extremely potent Plk1 inhibitor (IC 50 ~3 nM) with greater than 100-fold selectivity across a panel of 47 other kinases. It also potently inhibits the proliferation of many tumor cell lines in vitro , shows in vivo activity in tumor xenograft mouse models, and has appropriate physical and pharmacokinetic characteristics to support further evaluation as an anticancer agent.