Development of a Polo-like Kinase-1 Polo-Box Domain Inhibitor As a Tumor Growth Suppressor in Mice Models

Overview

Journal J Med Chem

Publisher American Chemical Society

Specialty Chemistry

Date 2020 Nov 3

PMID 33142063

Citations 6

Authors

Pethaiah Gunasekaran

Min Su Yim

Mija Ahn

Nak-Kyun Soung

Jung-Eun Park

Jaehi Kim

Geul Bang

Sang Chul Shin

Joonhyeok Choi

Minkyoung Kim

Hak Nam Kim

Young-Ho Lee

Young-Ho Chung

Kyeong Lee

Eunice EunKyeong Kim

Young-Ho Jeon

Min Ju Kim

Kyeong-Ryoon Lee

Bo-Yeon Kim

Kyung S Lee

Eun Kyoung Ryu

Jeong Kyu Bang

Affiliations

Soon will be listed here.

Abstract

Polo-like kinase-1 (Plk1) plays a key role in mitosis and has been identified as an attractive anticancer drug target. Plk1 consists of two drug-targeting sites, namely, N-terminal kinase domain (KD) and C-terminal polo-box domain (PBD). As KD-targeting inhibitors are associated with severe side effects, here we report on the pyrazole-based Plk1 PBD inhibitor, KBJK557, which showed a remarkable anticancer effect by inducing Plk1 delocalization, mitotic arrest, and apoptosis in HeLa cells. Further, optical imaging analysis and antitumorigenic activities in mouse xenograft models demonstrate that KBJK557 preferentially accumulates in cancer cells and selectively inhibits cancer cell proliferation. Pharmacokinetic profiles and partition coefficients suggest that KBJK557 was exposed in the blood and circulated through the organs with an intermediate level of clearance (, 7.73 h). The present investigation offers a strategy for specifically targeting cancer using a newly identified small-molecule inhibitor that targets the Plk1 PBD.

Citing Articles

Leveraging the Fragment Molecular Orbital Method to Explore the PLK1 Kinase Binding Site and Polo-Box Domain for Potent Small-Molecule Drug Design.

Jin H, Kim J, Lee O, Kim H, No K Int J Mol Sci. 2023; 24(21).

PMID: 37958623 PMC: 10650754. DOI: 10.3390/ijms242115639.

Specific inhibition of an anticancer target, polo-like kinase 1, by allosterically dismantling its mechanism of substrate recognition.

Park J, Kirsch K, Lee H, Oliva P, Il Ahn J, Ravishankar H Proc Natl Acad Sci U S A. 2023; 120(35):e2305037120.

PMID: 37603740 PMC: 10629583. DOI: 10.1073/pnas.2305037120.

Structural Optimization and Anticancer Activity of Polo-like Kinase 1 (Plk1) Polo-Box Domain (PBD) Inhibitors and Their Prodrugs.

Park J, Lee H, Oliva P, Kirsch K, Kim B, Il Ahn J ACS Pharmacol Transl Sci. 2023; 6(3):422-446.

PMID: 36926457 PMC: 10012257. DOI: 10.1021/acsptsci.2c00250.

Novel Macrocyclic Peptidomimetics Targeting the Polo-Box Domain of Polo-Like Kinase 1.

Ryu S, Park J, Ham Y, Lim D, Kwiatkowski N, Kim D J Med Chem. 2022; 65(3):1915-1932.

PMID: 35029981 PMC: 10411393. DOI: 10.1021/acs.jmedchem.1c01359.

A Comparison between Enrichment Optimization Algorithm (EOA)-Based and Docking-Based Virtual Screening.

Spiegel J, Senderowitz H Int J Mol Sci. 2022; 23(1).

PMID: 35008467 PMC: 8744642. DOI: 10.3390/ijms23010043.

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