Investigating Abbapolin PLK1 Polo Box Domain inhibitors as potential therapeutics for colorectal cancers

Polo-like kinase 1 (PLK1) is a central player in regulating entry into and progression through mitosis. Many studies have validated PLK1 as an anti-tumor drug target, and its inhibition is potently anti-proliferative to cancer cells. We have discovered a series of compounds named abbapolins that bind potently to the polo-box domain of PLK1 through a cryptic pocket and which induce proteasome mediated degradation of the PLK1 protein in a dose dependent manner without an E3-recruiting ligand as required for PROTACs. Abbapolins are able to engage PLK1 in cells, inhibit the phosphorylation of a PLK1 specific marker while having good pharmacokinetic properties and potently inhibiting the proliferation of prostate cancer cell lines in vitro and in vivo. As a result of these exciting observations, we propose to further develop the abbapolin PBD inhibitors and degraders of PLK1 as colorectal cancer therapeutics with a unique mechanism of action, laying the groundwork for preclinical and clinical development of the abbapolins. The aims of this application will be 1) medicinal chemistry optimization of abbapolin leads and 2) investigate their activity against colorectal cancers (CRC) including a panel of patient derived organoids, a powerful in vitro resource for identifying sensitive tumors and prioritizing them for future xenograft studies.