Identification and structure-function analysis of subfamily selective G protein-coupled receptor kinase inhibitors.
Identification and structure-function analysis of subfamily selective G protein-coupled receptor kinase inhibitors.
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DOI：
10.1021/cb5006323
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发表时间：
2015-01-16
影响因子：
4
通讯作者：
Tesmer, John J. G.
中科院分区：
文献类型：
--
作者：
Homan, Kristoff T.;Larimore, Kelly M.;Elkins, Jonathan M.;Szklarz, Marta;Knapp, Stefan;Tesmer, John J. G.
G蛋白偶联受体激酶(GRKs)亚家族的选择性抑制剂将作为有用的化学探针，并为从心力衰竭到帕金森病的治疗应用提供线索。为了确定这些抑制物，差示扫描荧光法被用来筛选一组已知的蛋白激酶抑制剂，它们可以提高两个最普遍表达的GRK：GRK2和GRK5的熔点。对14个最稳定的HIT进行的酶分析表明，其中3个对单个GRK具有纳摩尔抑制效力，其中一些表现出数量级的选择性。大多数已鉴定的化合物可分为两类：对GRK2有选择性的含吲唑/二氢嘧啶的化合物和对GRK1和GRK5有较强抑制作用但选择性较低的含吡咯并嘧啶的化合物。GSK180736A和GSK2163632A分别与GRK2和GRK1共晶，测得它们的原子结构间距分别为2.6和1.85；GSK180736A是一种Rho相关的含有卷曲的蛋白激酶抑制剂，它与GRK2的结合方式类似于帕罗西汀，而GSK2163632A是一种胰岛素样生长因子1受体抑制剂，它占据了GRK活性部位裂隙的一个新区域，很可能被利用来实现更高的选择性。然而，这两种化合物都没有比它们最初的靶点更有效地抑制GRK。这些数据为未来合理设计更有效和更有选择性的GRK抑制剂提供了基础。
Selective inhibitors of individual subfamilies of G protein-coupled receptor kinases (GRKs) would serve as useful chemical probes as well as leads for therapeutic applications ranging from heart failure to Parkinson’s disease. To identify such inhibitors, differential scanning fluorimetry was used to screen a collection of known protein kinase inhibitors that could increase the melting points of the two most ubiquitously expressed GRKs: GRK2 and GRK5. Enzymatic assays on 14 of the most stabilizing hits revealed that three exhibit nanomolar potency of inhibition for individual GRKs, some of which exhibiting orders of magnitude selectivity. Most of the identified compounds can be clustered into two chemical classes: indazole/dihydropyrimidine-containing compounds that are selective for GRK2 and pyrrolopyrimidine-containing compounds that potently inhibit GRK1 and GRK5 but with more modest selectivity. The two most potent inhibitors representing each class, GSK180736A and GSK2163632A, were cocrystallized with GRK2 and GRK1, and their atomic structures were determined to 2.6 and 1.85 Å spacings, respectively. GSK180736A, developed as a Rho-associated, coiled-coil-containing protein kinase inhibitor, binds to GRK2 in a manner analogous to that of paroxetine, whereas GSK2163632A, developed as an insulin-like growth factor 1 receptor inhibitor, occupies a novel region of the GRK active site cleft that could likely be exploited to achieve more selectivity. However, neither compound inhibits GRKs more potently than their initial targets. This data provides the foundation for future efforts to rationally design even more potent and selective GRK inhibitors.
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影响因子：
2.7
作者：
Bosanac, Todd;Hickey, Eugene R.;Young, Erick R. R.
通讯作者：
Young, Erick R. R.
影响因子：
--
作者：
Genick, Christine Clougherty;Barlier, Danielle;Ottl, Johannes
通讯作者：
Ottl, Johannes
影响因子：
46.9
作者：
通讯作者：
--
DOI：
10.1107/s0907444904019158
发表时间：
2004-12-01
影响因子：
2.2
作者：
Emsley, P;Cowtan, K
通讯作者：
Cowtan, K
影响因子：
--
作者：
Fedorov O;Huber K;Eisenreich A;Filippakopoulos P;King O;Bullock AN;Szklarczyk D;Jensen LJ;Fabbro D;Trappe J;Rauch U;Bracher F;Knapp S
通讯作者：
Knapp S