Identification of potent DUSP1 phosphatase allosteric inhibitors with structure-based virtual screening and verification with in vitro cell assay

Abstract

Mitogen-activated protein kinases (MAPKs) regulate cell proliferation, differentiation, metabolism, survival, apoptosis, and immune response. Therefore, The regulatory role of MAPKs is very important to cell signalling, and related to various diseases. Among the many MAPKs, the c-Jun N-terminal kinase (JNK) is regulated by DUSP1. Recent research has shown that DUSP1 is overexpressed in many cancers. DUSP1 has proved to be an attractive target for the development of therapeutics for the treatment of cancer. There were a lot of efforts to develop the small-molecule inhibitors that target the active site pocket of DUSP1. However, the inhibitors have structural limits with potency, selectivity and membrane permeability. Here, we have been able to identify the novel allosteric inhibitors of DUSP1 by virtual screening. Through In vitro cell assay and In vitro enzyme assay, we were able to show the effectiveness of the chemicals. Therefore, we assure that the small molecules deserve considerable allosteric inhibitors for further development by structure-activity relationship studies to develop therapeutics for cancers.