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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 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.
摘要：
人眼缺失（EYA）蛋白具有Tyr磷酸酶活性，这对许多癌症和转移促进活动至关重要，使其成为癌症治疗的有吸引力的目标。在这项工作中,我们证明EYA2的抑制剂结合形式不利于与Mg2+结合，这对于Tyr磷酸酶活性是必不可少的。我们进一步描述了这类变构抑制剂的表征和优化。合成了一系列类似物以提高抑制剂的效力并阐明结构-活性关系。两种共晶体结构证实了这类抑制剂的结合模式。我们的药物化学，结构,生物化学，和生物物理研究提供了对EYA2与这些变构抑制剂的分子相互作用的见解。来自本研究的化合物可用于探索正常和癌细胞中EYA2的Tyr磷酸酶活性的功能，并用作筛选或开发变构磷酸酶抑制剂的参考化合物。最后,本研究中报道的共晶结构将有助于针对EYA2的基于结构的药物发现。
