Generation of Highly Selective, Potent, and Covalent G Protein-Coupled Receptor Kinase 5 Inhibitors

The ability of G protein-coupled receptor (GPCR) kinases (GRKs) to regulate the desensitization of GPCRs has made GRK2 and GRK5 attractive targets for treating diseases such as heart failure and cancer. Previously, our work showed that Cys474, a GRK5 subfamily-specific residue located on a flexible loop adjacent to the active site, can be used as a covalent handle to achieve selective inhibition of GRK5 over GRK2 subfamily members. However, the potency of the most selective inhibitors remained modest. Herein, we describe a successful campaign to adapt an indolinone scaffold with covalent warheads, resulting in a series of 2-haloacetyl-containing compounds that react quickly and exhibit three orders of magnitude selectivity for GRK5 over GRK2 and low nanomolar potency. They however retain a similar selectivity profile across the kinome as the core scaffold, which was based on Sunitinib.

G蛋白偶联受体（G protein-coupled receptor，GPCR）激酶（G protein-coupled receptor kinases，GRKs）对GPCR脱敏作用的调控功能，使得GRK2与GRK5成为心力衰竭、癌症等疾病的极具吸引力的治疗靶点。此前本团队的研究显示，位于活性位点旁柔性环上的GRK5亚家族特异性残基半胱氨酸474（Cys474），可作为共价结合锚点，实现相较于GRK2亚家族成员的GRK5选择性抑制。然而，目前选择性最优的抑制剂其活性仍较为有限。本文中，我们报道了一项成功的研发策略：对带有共价弹头的吲哚酮（indolinone）骨架进行改造，得到一系列含2-卤代乙酰基的化合物。这类化合物反应迅速，对GRK5的选择性较GRK2高出三个数量级，且抑制活性达到低纳摩尔级。不过，这类化合物在整个激酶组中的选择性谱与以舒尼替尼（Sunitinib）为基础构建的核心骨架保持一致。