7F8H

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

Summary for 7F8H

• Entry DOI: 10.2210/pdb7f8h/pdb
• Descriptor: Eyes absent homolog 2, 3-fluoranyl-~{N}-[(~{E})-(5-pyridin-2-ylsulfanylfuran-2-yl)methylideneamino]benzamide (2 entities in total)
• Functional Keywords: eya2, eyes absent protein, phosphatase, transcription coactivator, transcription
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 3
• Total formula weight: 100103.12

Authors

Anantharajan, J.,Baburajendran, N. (deposition date: 2021-07-02, release date: 2021-12-29, Last modification date: 2023-11-29)

Primary citation

Anantharajan, J.,Baburajendran, N.,Lin, G.,Loh, Y.Y.,Xu, W.,Ahmad, N.H.B.,Liu, S.,Jansson, A.E.,Kuan, J.W.L.,Ng, E.Y.,Yeo, Y.K.,Hung, A.W.,Joy, J.,Hill, J.,Ford, H.L.,Zhao, R.,Keller, T.H.,Kang, C.
Structure-activity relationship studies of allosteric inhibitors of EYA2 tyrosine phosphatase.
Protein Sci., 31:422-431, 2022

PubMed 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 Mg , 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 these allosteric inhibitors. The compounds derived from this study are useful for exploring the function of the Tyr phosphatase activity of EYA2 in normal and cancerous cells and serve as reference compounds for screening or developing allosteric phosphatase inhibitors. Finally, the co-crystal structures reported in this study will aid in structure-based drug discovery against EYA2.

PubMed: 34761455
DOI: 10.1002/pro.4234

Experimental method

X-RAY DIFFRACTION (3.3 Å)