Members of the polo-like kinase (Plk) family of serine/threonine protein kinases (Plk1 – 5) play crucial roles in cell cycle regulation and proliferation. Among them, Plk1 is recognized as an anticancer drug target. Plk1 contains multiple structural components that are important for its proper biological function. These include an N-terminal catalytic domain and a C-terminal non-catalytic polo-box domain (PBD). The PBD binds to phosphothreonine (pT)- and phosphoserine-containing sequences. Blocking PBD-dependent interactions offers a potential means of down-regulating Plk1 function that is distinct from targeting its ATP-binding site. Previously, we demonstrated by tethering phenylalkyl chains from the N(π)-position of the His residue in the polo-box interacting protein 1 (PBIP1)-derived 5-mer peptide “PLHSpT”, that we were able to access a hydrophobic cryptic" binding pocket on the surface of the PBD, and in so doing enhance binding affinities by approximately 1000-fold. More recently, we optimized these PBD-ligand interactions using an oxime ligation-based strategy. We report our application of azide-alkyne cycloaddition reactions to prepare triazole-containing PBD-binding antagonists. Some of these ligands retain the high PBD-binding affinity of the parent peptide, while showing desirable enhanced selectivity for the PBD of Plk1 relative to the PBDs of Plk2 and Plk3.

Development of highly selective 1,2,3-triazole-containing peptidic polo-like kinase 1 polo-box domain-binding inhibitors

Macromolecular Chemistry: The Second Century

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ACS Spring 2020 National Meeting & Expo

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.