Development of Highly Selective 1,2,3-Triazole-containing Peptidic Polo-like Kinase 1 Polo-box Domain-binding Inhibitors

Overview

Journal Molecules

Publisher MDPI

Specialty Biology

Date 2019 Apr 25

PMID 31014020

Citations 3

Authors

Xue Zhi Zhao

Kohei Tsuji

David Hymel

Terrence R Burke Jr

Affiliations

Soon will be listed here.

Abstract

Members of the polo-like kinase (Plk) family of serine/threonine protein kinases play crucial roles in cell cycle regulation and proliferation. Of the five Plks (Plk1-5), 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 alkylphenyl chains from the (π)-position of the His residue in the 5-mer 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. Herein, using azide-alkyne cycloaddition reactions, we explore new 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.

Citing Articles

Affinity enhancement of polo-like kinase 1 polo box domain-binding ligands by a bivalent approach using a covalent kinase-binding component.

Tsuji K, Tamamura H, Burke Jr T RSC Chem Biol. 2024; 5(8):721-728.

PMID: 39092437 PMC: 11289893. DOI: 10.1039/d4cb00031e.

Identification of PLK1-PBD Inhibitors from the Library of Marine Natural Products: 3D QSAR Pharmacophore, ADMET, Scaffold Hopping, Molecular Docking, and Molecular Dynamics Study.

Zhou N, Zheng C, Tan H, Luo L Mar Drugs. 2024; 22(2).

PMID: 38393054 PMC: 10890274. DOI: 10.3390/md22020083.

Design and synthesis of a new orthogonally protected glutamic acid analog and its use in the preparation of high affinity polo-like kinase 1 polo-box domain - binding peptide macrocycles.

Hymel D, Tsuji K, Grant R, Chingle R, Kunciw D, Yaffe M Org Biomol Chem. 2021; 19(36):7843-7854.

PMID: 34346472 PMC: 8456285. DOI: 10.1039/d1ob01120k.

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