Abstract 2156: Targeting polo-like kinase 1 with novel inhibitors of the polo-box domain.

Abstract Polo-like Kinase 1 (PLK1) is a central player in cell cycle regulation and mitotic progression. Observations that PLK1 is over-expressed in many cancer types have led to efforts to target this protein therapeutically. Several ATP-binding site inhibitors of PLK1 have advanced to clinical trials, but these compounds inhibit at least three of the four known mammalian PLKs to varying degrees. This is problematic because, for example, PLK3 acts as a tumor suppressor and has opposing functions to PLK1. Moreover, a recent study identified a single point mutation near the ATP binding site that renders PLK1 resistant to several structurally unrelated ATP-based inhibitors, while retaining kinase activity. The Polo-box domain (PBD) of each PLK is a phospho-peptide binding motif that determines substrate recognition and subcellular localization. Our approach is to target the PBD of PLK1 to achieve desired PLK1 selectivity and improve efficacy. We recently reported a structure-activity relationship for a series of fragment-ligated inhibitory peptides (FLIPs) designed to be selective for the PBD of PLK1 (Mol. Cancer Ther., 2012, 11, 1683-1692). Our most potent compound in that class possessed a binding affinity to the PLK1 PBD (IC50 value of 8.6 μM), and insignificant levels of PLK3 binding up to 600 μM, which represents at least a 100-fold selectivity. The compound was able to induce cellular phenotypes consistent with a PLK1 knockdown, including aberrant mitoses and induction of apoptosis. Here, we report the development of new FLIP analogues with improved potency in binding to the PLK1 PBD. Specifically, we have designed, synthesized, and tested new benzoic acid capping groups to exploit a hydrophobic cleft in the PBD binding site. This newer generation of compounds possess binding affinities to the PLK1 PBD with IC50 values below 1 μM. Studies are in progress to determine PLK1 selectivity and activity in cells. Future studies will explore the ability of PBD-targeted compounds to circumvent resistance to ATP-based compounds. Citation Format: Merissa Baxter, Sandra Craig, Campbell McInnes, Michael D. Wyatt. Targeting polo-like kinase 1 with novel inhibitors of the polo-box domain. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2156. doi:10.1158/1538-7445.AM2013-2156