Screening of DUSP1 allosteric inhibitors by using chemical library and analysis of cellular effect.

Abstract

The MAPK phosphatase DUSP1(MKP1) is overexpressed in many diseases including breast cancer, pancreatic cancer, and hepatitis C virus. Therefore DUSP1 inhibitor is very important for DUSP1 overexpressed diseases. However, the currently identified DUSP1 inhibitor has been difficult to use in cells. Because of the following reasons, first, it is difficult for the DUSP1 inhibitor to enter into the DUSP1 active site. Second, DUSP1 has an active site that is similar in structure to other DUSPs. Finally, The DUSP1 inhibitor has difficulty penetrating cells because of its charged nature. To solve these problems, we must find the allosteric inhibitors of DUSP1. We used the chemicals provided by Korean research institute of chemical technology(KRICT) to screen for the DUSP1 allosteric inhibitor. The chemicals that inhibited DUSP1 in screening were tested if they can inhibit DUSP1 in cells. Finally, we checked whether they are allosteric inhibitors or not by enzyme kinetics assay. The DUSP1 allosteric inhibitor is expected to solve the DUSP1 overexpression in many diseased cells.