NCI-Designated Cancer Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, USA.
Methods Mol Biol. 2023;2706:167-175. doi: 10.1007/978-1-0716-3397-7_12.
Striatal-enriched protein tyrosine phosphatase (STEP) is a brain-specific enzyme that regulates the signaling molecules that control synaptic plasticity and neuronal function. Dysregulation of STEP is linked to the pathophysiology of Alzheimer's disease and other neuropsychiatric disorders. Experimental results from neurological deficit disease models suggest that the modulation of STEP could be beneficial in a number of these disorders. This prompted our work to identify small-molecule modulators of STEP to provide the foundation of a drug discovery program. As a component of our testing funnel to identify small-molecule STEP inhibitors, we have developed a cellular target engagement assay that can identify compounds that interact with STEP. We provide a comprehensive protocol to enable the use of this miniaturized assay, and we demonstrate its utility to benchmark the binding of newly discovered compounds.
纹状体富集蛋白酪氨酸磷酸酶（STEP）是一种大脑特异性酶，可调节控制突触可塑性和神经元功能的信号分子。STEP 的失调与阿尔茨海默病和其他神经精神疾病的病理生理学有关。神经病学缺陷疾病模型的实验结果表明，调节 STEP 可能对许多这些疾病有益。这促使我们努力识别 STEP 的小分子调节剂，为药物发现计划提供基础。作为识别小分子 STEP 抑制剂的测试漏斗的一部分，我们开发了一种细胞靶标结合测定法，可以鉴定与 STEP 相互作用的化合物。我们提供了一个全面的方案来使用这个微型化的测定法，并证明其可用于基准新发现化合物的结合。
