Generation of Highly Selective, Potent, and Covalent G Protein-Coupled Receptor Kinase 5 Inhibitors.
Generation of Highly Selective, Potent, and Covalent G Protein-Coupled Receptor Kinase 5 Inhibitors.
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高选择性、有效和共价G蛋白偶联受体激酶5抑制剂的产生。
DOI：
10.1021/acs.jmedchem.0c01522
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发表时间：
2021-01-14
影响因子：
7.3
通讯作者：
White AD
中科院分区：
文献类型：
--
作者：
Rowlands RA;Chen Q;Bouley RA;Avramova LV;Tesmer JJG;White AD
G蛋白偶联受体激酶(GRKs)调节GPCRs脱敏的能力使GRK2和GRK5成为治疗心力衰竭和癌症等疾病的有吸引力的靶点。此前，我们的工作表明，位于活性位点附近的柔性环上的GRK5亚家族特异性残基Cys474可以作为共价柄，实现对GRK2亚家族成员的选择性抑制。然而，最具选择性的抑制剂的效力仍然不大。在这里，我们描述了一项成功的活动，使具有共价弹头的吲哚酮支架得到一系列含有2-卤代乙酰的化合物，这些化合物反应迅速，对GRK5的选择性比GRK2高三个数量级，并且具有低纳摩尔效力。然而，它们在整个Kinome上保留了与基于Sunitinib的核心支架类似的选择性分布。
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.
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影响因子：
4.8
作者：
Homan, Kristoff T.;Waldschmidt, Helen V.;Tesmer, John J. G.
通讯作者：
Tesmer, John J. G.
影响因子：
7.3
作者：
Waldschmidt HV;Homan KT;Cato MC;Cruz-Rodríguez O;Cannavo A;Wilson MW;Song J;Cheung JY;Koch WJ;Tesmer JJ;Larsen SD
通讯作者：
Larsen SD
影响因子：
3.7
作者：
Schlegel P;Reinkober J;Meinhardt E;Tscheschner H;Gao E;Schumacher SM;Yuan A;Backs J;Most P;Wieland T;Koch WJ;Katus HA;Raake PW
通讯作者：
Raake PW
影响因子：
20.1
作者：
Gold JI;Gao E;Shang X;Premont RT;Koch WJ
通讯作者：
Koch WJ
影响因子：
3.7
作者：
Lee, Jeong Hyun;Seo, Ho Won;Lee, Byung Ho
通讯作者：
Lee, Byung Ho