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Discovery of Non‐ATP‐Competitive Inhibitors of Polo‐like Kinase 1
Author(s) -
Yun Taikangxiang,
Qin Tan,
Liu Ying,
Lai Luhua
Publication year - 2016
Publication title -
chemmedchem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.817
H-Index - 100
eISSN - 1860-7187
pISSN - 1860-7179
DOI - 10.1002/cmdc.201600051
Subject(s) - plk1 , polo like kinase , kinase , biochemistry , serine , docking (animal) , binding site , chemistry , enzyme , protein kinase domain , virtual screening , threonine , protein kinase a , phosphorylation , biology , drug discovery , mutant , cell , cell cycle , medicine , nursing , gene
Polo‐like kinase 1 (Plk1) is an evolutionarily conserved serine/threonine kinase, and its N‐terminal kinase domain (KD) controls cell signaling through phosphorylation. Inhibitors of Plk1 are potential anticancer drugs. Most known Plk1 KD inhibitors are ATP‐competitive compounds, which may suffer from low selectivity. In this study we discovered novel non‐ATP‐competitive Plk1 KD inhibitors by virtual screening and experimental studies. Potential binding sites in Plk1 KD were identified by using the protein binding site detection program Cavity. The identified site was subjected to molecular‐docking‐based virtual screening. The activities of top‐ranking compounds were evaluated by in vitro enzyme assay with full‐length Plk1 and direct binding assay with Plk1 KD. Several compounds showed inhibitory activity, and the most potent was found to be 3‐((2‐oxo‐2‐(thiophen‐2‐yl)ethyl)thio)‐6‐(pyridin‐3‐ylmethyl)‐1,2,4‐triazin‐5(4 H )‐one (compound 4 ) with an IC 50 value of 13.1±1.7 μ m . Our work provides new insight into the design of kinase inhibitors that target non‐ATP binding sites.