Discovery of Non‐ATP‐Competitive Inhibitors of Polo‐like Kinase 1. (8th March 2016) - Yun, Taikangxiang
Abstract: 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 (compound4 ) with an IC50 value of 13.1±1.7 μm . Our work provides new insight into the design of kinase inhibitors that target non‐ATP binding sites. Abstract : New binding site inhibitors : Polo‐like kinase 1 (Plk1) inhibitors that target the ATP binding site of the kinase domain (KD) have been developed to treat cancers. Until now, non‐ATP‐competitive inhibitors of Plk1 KD have not been reported. Through virtual screening and experimental studies, we identified a new binding site in Plk1 KD and successfully applied it to the discovery of non‐ATP‐competitive Plk1 inhibitors.