Excessive activity of striatal-enriched protein tyrosine phosphatase (STEP) in the brain has been detected in numerous neuropsychiatric disorders including Alzheimer’s disease. Notably, knockdown of STEP in an Alzheimer mouse model effected an increase in the phosphorylation levels of downstream STEP substrates and a significant reversal in the observed cognitive and memory deficits. These data point to the promising potential of STEP as a target for drug discovery in Alzheimer’s treatment. We previously reported a substrate-based approach to the development of low molecular weight STEP inhibitors with K_i values as low as 7.8 μM. Herein, we disclose the first X-ray crystal structures of inhibitors bound to STEP and the surprising finding that they occupy noncoincident binding sites. Moreover, we utilize this structural information to optimize the inhibitor structure to achieve a K_i of 110 nM, with 15–60-fold selectivity across a series of phosphatases.

中文翻译：

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纹状体富集蛋白酪氨酸磷酸酶抑制剂的X射线表征和基于结构的优化

在包括阿尔茨海默氏病在内的许多神经精神疾病中已检测到大脑中纹状体富集的蛋白酪氨酸磷酸酶（STEP）的过度活性。值得注意的是，在阿尔茨海默病小鼠模型中，STEP的敲低导致下游STEP底物的磷酸化水平增加，并且观察到的认知和记忆缺陷明显逆转。这些数据表明，STEP作为阿尔茨海默氏病治疗药物发现目标的潜力巨大。我们之前曾报道过使用基于底物的方法开发具有K _i的低分子量STEP抑制剂值低至7.8μM。在此，我们公开了与STEP结合的抑制剂的第一个X射线晶体结构，以及令人惊讶的发现，即它们占据了非一致的结合位点。此外，我们利用这种结构信息来优化抑制剂结构，以使K _i达到110 nM，在一系列磷酸酶上具有15-60倍的选择性。