Structure-activity relationship studies of allosteric inhibitors of EYA2 tyrosine phosphatase.

ABSTRACT: Human eyes absent (EYA) proteins possess Tyr phosphatase activity, which is critical for numerous cancer and metastasis promoting activities, making it an attractive target for cancer therapy. In this work, we demonstrate that the inhibitor-bound form of EYA2 does not favour binding to Mg²⁺ , which is indispensable for the Tyr phosphatase activity. We further describe characterization and optimization of this class of allosteric inhibitors. A series of analogues were synthesized to improve potency of the inhibitors and to elucidate structure-activity relationships. Two co-crystal structures confirm the binding modes of this class of inhibitors. Our medicinal chemical, structural, biochemical, and biophysical studies provide insight into the molecular interactions of EYA2 with th

SUBMITTER: Anantharajan J 

PROVIDER: S-EPMC8819961 | biostudies-literature | 2022 Feb

REPOSITORIES: biostudies-literature