PKIS deep dive yields a chemical starting point for dark kinases and a cell active BRSK2 inhibitor.
PKIS deep dive yields a chemical starting point for dark kinases and a cell active BRSK2 inhibitor.
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DOI：
10.1038/s41598-020-72869-9
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发表时间：
2020-09-28
影响因子：
4.6
通讯作者：
Axtman AD
中科院分区：
文献类型：
--
作者：
Tamir TY;Drewry DH;Wells C;Major MB;Axtman AD
已发表的激酶抑制剂集（PKIS）是一个公开的化学基因组学文库，由葛兰素史克（GSK）在2011年至2015年期间分发给300多个实验室，并由SGC-ESTA在2015年至2017年期间分发。筛选这个注释良好、已发表的激酶抑制剂库，在不同的治疗和科学领域、资助的应用、出版物中产生了大量数据，并提供了有影响力的临床前结果。GW 296115是一种化合物，基于其对260种人类激酶的分析后有希望的选择性而被纳入PKIS。在此，我们提供了403种野生型人类激酶的更全面的分析数据和GW 296115的后续酶筛选结果。对GW 296115的更彻底的研究证实了它是一种强效激酶抑制剂，包括在原始的260种激酶中鉴定的BRSK 1和BRSK 2，以及它强效抑制的其他表面激酶。基于这些新的激酶组范围的筛选结果，我们报告说，GW 296115是一种抑制剂的几个成员的照明的药物基因组（IDG）名单研究不足的黑暗激酶。具体来说，我们的研究结果确立了GW 296115作为一种有效的先导化学工具，可抑制六种IDG激酶，IC 50值小于100 nM。重点研究确定GW 296115具有细胞活性，并直接与BRSK 2结合。进一步的评估表明，GW 296115下调BRSK 2驱动的磷酸化和下游信号传导。因此，我们提出GW 296115作为一种细胞活性化学工具，可用于询问BRSK 2的不良特征功能。
The Published Kinase Inhibitor Set (PKIS) is a publicly-available chemogenomic library distributed to more than 300 laboratories by GlaxoSmithKline (GSK) between 2011 and 2015 and by SGC-UNC from 2015 to 2017. Screening this library of well-annotated, published kinase inhibitors has yielded a plethora of data in diverse therapeutic and scientific areas, funded applications, publications, and provided impactful pre-clinical results. GW296115 is a compound that was included in PKIS based on its promising selectivity following profiling against 260 human kinases. Herein we present more comprehensive profiling data for 403 wild type human kinases and follow-up enzymatic screening results for GW296115. This more thorough investigation of GW296115 has confirmed it as a potent inhibitor of kinases including BRSK1 and BRSK2 that were identified in the original panel of 260 kinases as well as surfaced other kinases that it potently inhibits. Based on these new kinome-wide screening results, we report that GW296115 is an inhibitor of several members of the Illuminating the Druggable Genome (IDG) list of understudied dark kinases. Specifically, our results establish GW296115 as a potent lead chemical tool that inhibits six IDG kinases with IC50 values less than 100 nM. Focused studies establish that GW296115 is cell active, and directly engages BRSK2. Further evaluation showed that GW296115 downregulates BRSK2-driven phosphorylation and downstream signaling. Therefore, we present GW296115 as a cell-active chemical tool that can be used to interrogate the poorly characterized function(s) of BRSK2.
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DOI：
10.1126/science.1196371
发表时间：
2011-01-28
期刊：
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通讯作者：
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