Inhibitor Development Against the Wip1 Phosphatase

Division Of Basic Sciences - Nci

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Abstract

The goal of this work is to develop an inhibitor of the Wip1 protein. Wip1 is a serine/threonine phosphatase enzyme in the PP2C family. It is transcriptionally induced after DNA damage in a p53-dependent manner, and acts as a crucial pivot-point in cancerous cell transformation. For example, Wip1 indirectly suppresses p53 function by inactivating p38 MAP Kinase. Additionally, Wip1 inhibits Chk2 Kinase, thus removing another block to cell growth. Recently, we determined the crystal structure of Wip1, giving a conformation of the reaction specificity determining B-loop, and indicating a LYS-CYS NOS bridge that may confer redox regulation.