The ability of G protein-coupled receptor (GPCR) kinases (GRKs) to regulate desensitization of GPCRs has made GRK2 and GRK5 attractive targets for treating heart failure and other diseases such as cancer. Although advances have been made toward developing inhibitors that are selective for GRK2, there have been far fewer reports of GRK5 selective compounds. Herein, we describe the development of GRK5 subfamily selective inhibitors, 5 and 16d that covalently interact with a nonconserved cysteine (Cys474) unique to this subfamily. Compounds 5 and 16d feature a highly amenable pyrrolopyrimidine scaffold that affords high nanomolar to low micromolar activity that can be easily modified with Michael acceptors with various reactivities and geometries. Our work thereby establishes a new pathway toward further development of subfamily selective GRK inhibitors and establishes Cys474 as a new and useful covalent handle in GRK5 drug discovery.

中文翻译：

---

选择性，共价G蛋白偶联的受体激酶5抑制剂的基于结构的设计。

G蛋白偶联受体（GPCR）激酶（GRKs）调节GPCR脱敏的能力使GRK2和GRK5成为治疗心力衰竭和其他疾病（例如癌症）的有吸引力的靶标。尽管在开发对GRK2具有选择性的抑制剂方面取得了进展，但有关GRK5选择性化合物的报道却很少。在本文中，我们描述了与该亚家族独特的非保守半胱氨酸（Cys474）共价相互作用的GRK5亚家族选择性抑制剂5和16d的开发。化合物5和16d具有高度适应性的吡咯并嘧啶支架，可提供高纳摩尔至低微摩尔活性，可通过具有各种反应性和几何结构的Michael受体轻松对其进行修饰。