Polo-like kinase 1 (PLK1) has many roles within the cell and is involved primarily in mitotic regulation and has been shown to be upregulated in cancer cells, making it a viable target for therapeutics. REplacement with Partial Ligand Alternatives through Computational Enrichment, REPLACE, is a method used to convert non-drug-like peptide inhibitors of protein-protein interactions into pharmaceutically acceptable compounds. Through this approach, we have developed drug-like inhibitors based on a 2-(4-AlkylBenzamido) Benzoic Acid (ABBA) pharmacophore which target the polo-box domain of PLK1 and thus in a non-ATP competitive manner . These compounds designated as abbapolins, have been shown to engage PLK1 at the cellular level, block phosphorylation of TCTP, a key substrate of PLK1, induce PLK1 degradation and are potently anti-proliferative in prostate cancer cell lines. Due to their promise in preliminary cellular models, selected abbapolins were further tested against the NCI-60 tumor cell panel and other cancers with poor prognosis. Promising results from this screening suggest that neuroblastoma, lung, colorectal and certain leukemias are the most sensitive cell lines and provide opportunities to further develop the abbapolins for difficult to treat and resistant tumors. We present the design and optimization of abbapolins to identify compounds with novel structures and improved drug-like properties which further establish the structure-activity, engagement of PLK1 and anti-proliferative activities against selected cell lines that represent therapeutically challenging cancers. Furthermore, these compounds will be used as chemical biology probes to understand the roles of the PBD in conformationally regulating PLK1 activity, through in vitro experiments and also specifically in the sensitive cell lines we are investigating.

Design and synthesis of optimized abbapolin inhibitors of the PLK1 polo-box domain based on results from NCI-60 cell line screening

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