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蛋白偶联受体激酶（G protein-coupled receptor kinases, GRKs）对G蛋白偶联受体（G protein-coupled receptor, GPCR）脱敏作用的调控能力，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。既往研究中，我们的工作发现，位于活性位点旁柔性环上的GRK5亚家族特异性残基Cys474可作为共价锚点，实现对GRK5相较于GRK2亚家族成员的选择性抑制。然而，目前选择性最高的抑制剂其活性效力仍较为有限。本文中，我们报道了一项成功的研发工作：对带有共价弹头的吲哚酮骨架进行改造，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的选择性相较GRK2高达三个数量级，且活性效力达到低纳摩尔级别。不过，相较于以舒尼替尼（Sunitinib）为基础开发的核心骨架，这类化合物在激酶组中仍保留了相似的选择性谱。