The development of small-molecule inhibitors targeting G protein-coupled receptor kinase 2 (GRK2) and G protein-coupled receptor kinase 5 (GRK5) for the treatment of chronic degenerative diseases has attracted wide attention. GRK2 and GRK5 can regulate essential physiological processes by phosphorylating G protein-coupled receptor (GPCR). Alterations in the functional levels of GRK2 and GRK5 have been found in a variety of chronic degenerative diseases, such as cardiovascular diseases, neurodegenerative diseases, cancers, type 2 diabetes, and rheumatoid arthritis (RA). Abnormal GRK2 and GRK5 expression contribute to the development of chronic degenerative diseases through environmental molecular mechanisms, making them promising molecular targets for treating chronic degenerative diseases. To date, many novel GRK2 and GRK5 inhibitors have been reported for the treatment of chronic degenerative diseases. We focus on the recent progress of single and dual-target inhibitors of GRK2/GRK5. This review summarizes the structural optimization rationale, structure-activity relationships (SARs), and the latest application in the treatment of chronic degenerative diseases. We believe it will shed light on the future development of small molecule inhibitors of GRK2 and GRK5, as well as the clinical applications in chronic degenerative diseases.

靶向G蛋白偶联受体激酶2（GRK2）和G蛋白偶联受体激酶5（GRK5）治疗慢性退行性疾病的小分子抑制剂的开发引起了广泛关注。GRK2 和 GRK5 可以通过磷酸化 G 蛋白偶联受体 (GPCR) 来调节基本的生理过程。已经在多种慢性退行性疾病中发现了 GRK2 和 GRK5 功能水平的改变，例如心血管疾病、神经退行性疾病、癌症、2 型糖尿病和类风湿性关节炎 (RA)。GRK2和GRK5的异常表达通过环境分子机制促进慢性退行性疾病的发展，使其成为治疗慢性退行性疾病的有希望的分子靶点。迄今为止，许多新型 GRK2 和 GRK5 抑制剂已被报道用于治疗慢性退行性疾病。我们关注 GRK2/GRK5 单靶点和双靶点抑制剂的最新进展。本综述总结了结构优化的原理、结构-活性关系 (SAR) 以及在慢性退行性疾病治疗中的最新应用。我们相信它将为GRK2和GRK5小分子抑制剂的未来发展以及在慢性退行性疾病中的临床应用提供启示。以及治疗慢性退行性疾病的最新应用。我们相信它将为GRK2和GRK5小分子抑制剂的未来发展以及在慢性退行性疾病中的临床应用提供启示。以及治疗慢性退行性疾病的最新应用。我们相信它将为GRK2和GRK5小分子抑制剂的未来发展以及在慢性退行性疾病中的临床应用提供启示。