G protein-coupled receptor kinase 5 (GRK5) has emerged as a potential drug development target against heart failure and cancer. A close homolog, GRK6 represents a therapeutic target for multiple myeloma. We have rationally designed a series of highly selective, potent, noncovalent, and drug-like GRK5 inhibitors. Several inhibitors exhibited low nanomolar GRK5 inhibition and high selectivity over GRK2, and, surprisingly, some were selective for GRK6. We determined high-resolution X-ray crystal structures of several inhibitors in complex with GRK5, which provide molecular insights into the ligand-binding site interactions responsible for GRK5 selectivity and potency.

中文翻译：

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一系列高效、选择性和药物样 G 蛋白偶联受体激酶 5 抑制剂的设计、合成和 X 射线结构研究


G 蛋白偶联受体激酶 5 （GRK5） 已成为治疗心力衰竭和癌症的潜在药物开发靶点。GRK6 是一种接近的同源物，代表多发性骨髓瘤的治疗靶点。我们合理设计了一系列高选择性、强效、非共价和类药的 GRK5 抑制剂。几种抑制剂表现出低纳摩尔 GRK5 抑制和对 GRK2 的高选择性，令人惊讶的是，有些抑制剂对 GRK6 具有选择性。我们确定了与 GRK5 复合物中几种抑制剂的高分辨率 X 射线晶体结构，这为负责 GRK5 选择性和效力的配体结合位点相互作用提供了分子见解。