Identification of FDA-Approved Small Molecules Capable of Disrupting the Calmodulin–Adenylyl Cyclase 8 Interaction through Direct Binding to Calmodulin,ACS Chemical Neuroscience

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Identification of FDA-Approved Small Molecules Capable of Disrupting the Calmodulin–Adenylyl Cyclase 8 Interaction through Direct Binding to Calmodulin
ACS Chemical Neuroscience ( IF 4.1 ) Pub Date : 2017-10-16 00:00:00 , DOI: 10.1021/acschemneuro.7b00349
Michael P. Hayes ₁ , Monica Soto-Velasquez ₂ , C. Andrew Fowler ₃ , Val J. Watts ₂ , David L. Roman _{1,

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Affiliation

Adenylyl cyclases (AC) catalyze the formation of cyclic AMP (cAMP) from ATP and are involved in a number of disease states, making them attractive potential drug targets. AC8, in particular, has been implicated in several neurological disorders. While development of small molecule AC inhibitors has generated some chemical leads, the lack of inhibitor specificity among AC family members has limited the identification of successful drug candidates. Therefore, finding alternative novel methods to suppress AC activity are needed. Because only AC1 and AC8 are robustly stimulated by calmodulin (CaM), we set out to explore the mechanism of disrupting the AC/CaM interaction as a way to selectively inhibit AC8. Through the development and implementation of a novel biochemical high-throughput-screening paradigm, we identified six small molecules from an FDA-approved compound library that are capable of disrupting the AC8/CaM interaction. These compounds were also shown to be able disrupt formation of this complex in cells, ultimately leading to decreased AC8 activity. Interestingly, further mechanistic analysis determined that these compounds functioned by binding to CaM and blocking its interaction with AC8. While these particular compounds could inhibit CaM interaction with both AC1 and AC8, they provide significant proof of concept for inhibition of ACs through disruption of CaM binding. These compounds, as dual AC1/AC8 inhibitors, provide important tools for probing pathological conditions where AC1/AC8 activity are enhanced, such as chronic pain and ethanol consumption. Furthermore, unlike tools such as genetic deletion, these compounds can be used in a dose-dependent fashion to determine the role of AC/CaM interactions in these pathologies.

中文翻译：

通过直接结合钙调蛋白可破坏钙调蛋白-腺苷酸环化酶8相互作用的FDA批准的小分子的鉴定

腺苷酸环化酶（AC）催化由ATP形成环状AMP（cAMP），并涉及多种疾病状态，使其成为具有吸引力的潜在药物靶标。特别地，AC8已经与几种神经系统疾病有关。虽然小分子AC抑制剂的开发已经产生了一些化学线索，但AC家庭成员之间抑制剂特异性的缺乏限制了成功候选药物的鉴定。因此，需要寻找抑制AC活性的替代性新方法。因为只有AC1和AC8是稳健在钙调蛋白（CaM）的刺激下，我们着手探讨破坏AC / CaM相互作用的机制，以此作为选择性抑制AC8的方法。通过开发和实施新型的生物化学高通量筛选范例，我们从FDA批准的化合物库中鉴定了6个能够破坏AC8 / CaM相互作用的小分子。这些化合物还被证明能够破坏细胞中这种复合物的形成，最终导致AC8活性降低。有趣的是，进一步的机理分析确定这些化合物通过与CaM结合并阻断其与AC8的相互作用而起作用。虽然这些特定的化合物可以抑制CaM与AC1和AC8的相互作用，但它们提供了通过破坏CaM结合来抑制AC的重要概念证明。这些化合物，作为双重AC1 / AC8抑制剂，它为探测AC1 / AC8活性增强的病理状况（例如慢性疼痛和乙醇消耗）提供了重要的工具。此外，与诸如遗传删除之类的工具不同，这些化合物可以剂量依赖的方式用于确定AC / CaM相互作用在这些病理中的作用。

更新日期：2017-10-17

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