8WFP

Crystal structure of polo-like kinase(PLK1)PBD in complex with DD-1

8WFP の概要

• エントリーDOI: 10.2210/pdb8wfp/pdb
• 分子名称: Serine/threonine-protein kinase PLK1, DD-1 (3 entities in total)
• 機能のキーワード: inhibitor, structural protein
• 由来する生物種: Homo sapiens (human); 詳細
• タンパク質・核酸の鎖数: 4
• 化学式量合計: 53422.76

構造登録者

Park, J.,La, Y.K.,Bang, J.K.,Lee, S.J. (登録日: 2023-09-20, 公開日: 2024-09-25, 最終更新日: 2024-11-13)

主引用文献

Gunasekaran, P.,Hwang, Y.S.,Lee, G.H.,Park, J.,Kim, J.G.,La, Y.K.,Park, N.Y.,Kothandaraman, R.,Yim, M.S.,Choi, J.,Kim, H.N.,Park, I.Y.,Lee, S.J.,Kim, M.H.,Cha-Molstad, H.,Shin, S.Y.,Ryu, E.K.,Bang, J.K.
Degradation of Polo-like Kinase 1 by the Novel Poly-Arginine N-Degron Pathway PROTAC Regulates Tumor Growth in Nonsmall Cell Lung Cancer.
J.Med.Chem., 67:3307-3320, 2024

PubMed Abstract: Polo-like kinase 1 (PLK1), which is crucial in cell cycle regulation, is considered a promising anticancer drug target. Herein, we present the N-degron pathway-based proteolysis targeting chimera (PROTAC) for PLK1 degradation, targeting the Polo-box domain (PBD). We identified DD-2 as the most potent PROTAC that selectively induces PLK1 degradation in cancer cells, including HeLa and nonsmall cell lung cancer (NSCLC), through the N-degron pathway. DD-2 exhibited significant in vitro anticancer effects, inducing G2/M arrest and apoptosis in HeLa and NSCLC cell lines. DD-2 showed significant tumor growth inhibition in a xenograft mouse model using HeLa and NSCLC cell lines, highlighting its potential in cancer treatment. Furthermore, the combination of DD-2 with tyrosine kinase inhibitor (TKI), osimertinib, effectively suppressed tumor growth in double-mutated H1975 cell lines, emphasizing DD-2's potential in combination cancer therapies. Collectively, this study demonstrates the potential of the N-degron pathway, especially using DD-2, for targeted cancer therapies.

PubMed: 38105611
DOI: 10.1021/acs.jmedchem.3c01493

実験手法

X-RAY DIFFRACTION (1.99 Å)