Efficient chemical library screening for WNK signaling inhibitors byinhibiting WNK-SPAK interaction

我们重点研究了在血压调节中起关键作用的无赖氨酸激酶（WNK）信号级联。抑制这种信号级联的药物可能是一类新的抗高血压药物。我们试图通过筛选破坏结合的化合物来发现WNK-SPAK结合的抑制剂。为此，我们开发了一种高通量的筛选方法，使用荧光相关光谱。作为筛选17，000种化合物的结果，我们发现了两种可重复破坏WNK与SPAK结合的新化合物。对种子化合物进行了结构修饰，得到了具有较高抑制活性的新化合物。

We focused on the With-no-lysine kinases (WNK) signaling cascade which has a pivotal role in regulating blood pressure. Agents that inhibit this signal cascade could be a new class of antihypertensive drugs. We sought to discover inhibitors of WNK-SPAK binding by screening chemical compounds that disrupt the binding. For this purpose, we developed a high-throughput screening method using fluorescent correlation spectroscopy. As a result of screening 17,000 compounds, we discovered two novel compounds that reproducibly disrupted the binding of WNK to SPAK. We then performed the modification of the seed compounds, and obtained novel compounds that exhibit the higher inhibitory activity.