Abstract 4993: Development of abbapolin inhibitors of the PLK1 PBD as potential therapeutics for prostate and other challenging cancers

Abstract

Polo-like kinase 1 (PLK1) has a plethora of roles within the cell of which mitotic regulation is the best characterized. This kinase is overexpressed and upregulated in cancer cells, making it an attractive target for therapeutics. Drug discovery efforts have mainly focused on the ATP binding site however have met with little clinical success to date. Targeting substrate recognition and subcellular localization through the Polo-Box domain represents an attractive alternative to generating PLK1 specific compounds and to avoid the tumor suppressor functions of PLK3. REplacement with Partial Ligand Alternatives through Computational Enrichment, REPLACE, is validated strategy used to convert peptide inhibitors of protein-protein interactions into more drug like compounds. Through the use of this methodology, we have discovered promising non-ATP competitive inhibitors based on a 2-(4-AlkylBenzamido) Benzoic Acid (ABBA) pharmacophore which bind to the polo-box domain of PLK1. These compounds, designated as abbapolins, engage PLK1 as evidenced by their ability to block phosphorylation of TCTP, a key substrate of PLK1, induce PLK1 degradation and are potently anti-proliferative in prostate cancer cell lines. Based on these observations, lead compounds were investigated further for their pharmacokinetic properties and in vivo efficacy and key compounds showed development potential based upon preliminary results. To further investigate their potential in other tumors, selected abbapolins were tested against the NCI-60 tumor cell panel and other cancers with poor prognosis. Results indicate that neuroblastoma, lung, colorectal and certain leukemias are the most sensitive cell lines and thus provide impetus to investigate the abbapolins for difficult to treat and resistant tumors. We present the further optimization of the abbapolins to determine their structure-activity relationship and identify compounds with novel structures and improved drug-like properties. This includes their ability to engage PLK1 and anti-proliferative activities against selected cell lines that represent therapeutically challenging cancers. Furthermore, these compounds serve as chemical biology probes to elucidate roles of the PBD in conformationally regulating PLK1 activity, through in vitro experiments and specifically in the abbapolin sensitive cell lines. Citation Format: Jessy Stafford, Danda Chapagai, George Merhej, Justin Pressley, Chintada Nageswara-Rao, Michael Wyatt, Campbell Mcinnes. Development of abbapolin inhibitors of the PLK1 PBD as potential therapeutics for prostate and other challenging cancers. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4993.