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Type II Kinase Inhibitors Targeting Cys-Gatekeeper Kinases Display Orthogonality with Wild Type and Ala/Gly-Gatekeeper Kinases
ACS Chemical Biology ( IF 3.5 ) Pub Date : 2018-09-21 00:00:00 , DOI: 10.1021/acschembio.8b00592 Cory A Ocasio 1 , Alexander A Warkentin 2 , Patrick J McIntyre 3 , Krister J Barkovich 2 , Clare Vesely 1 , John Spencer 4 , Kevan M Shokat 2 , Richard Bayliss 5
ACS Chemical Biology ( IF 3.5 ) Pub Date : 2018-09-21 00:00:00 , DOI: 10.1021/acschembio.8b00592 Cory A Ocasio 1 , Alexander A Warkentin 2 , Patrick J McIntyre 3 , Krister J Barkovich 2 , Clare Vesely 1 , John Spencer 4 , Kevan M Shokat 2 , Richard Bayliss 5
Affiliation
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Analogue-sensitive (AS) kinases contain large to small mutations in the gatekeeper position rendering them susceptible to inhibition with bulky analogues of pyrazolopyrimidine-based Src kinase inhibitors (e.g., PP1). This “bump-hole” method has been utilized for at least 85 of ∼520 kinases, but many kinases are intolerant to this approach. To expand the scope of AS kinase technology, we designed type II kinase inhibitors, ASDO2/6 (analogue-sensitive “DFG-out” kinase inhibitors 2 and 6), that target the “DFG-out” conformation of Cys-gatekeeper kinases with submicromolar potency. We validated this system in vitro against Greatwall kinase (GWL), Aurora-A kinase, and cyclin-dependent kinase-1 and in cells using M110C-GWL-expressing mouse embryonic fibroblasts. These Cys-gatekeeper kinases were sensitive to ASDO2/6 inhibition but not AS kinase inhibitor 3MB-PP1 and vice versa. These compounds, with AS kinase inhibitors, have the potential to inhibit multiple AS kinases independently with applications in systems level and translational kinase research as well as the rational design of type II kinase inhibitors targeting endogenous kinases.
中文翻译：
针对 Cys-Gatekeeper 激酶的 II 型激酶抑制剂与野生型和 Ala/Gly-Gatekeeper 激酶表现出正交性
类似物敏感（AS）激酶在看门位置含有大到小的突变，使得它们容易受到基于吡唑并嘧啶的Src激酶抑制剂的大类似物（例如PP1）的抑制。这种“凹凸孔”方法已用于 ∼520 种激酶中的至少 85 种，但许多激酶不耐受这种方法。为了扩展 AS 激酶技术的范围，我们设计了 II 型激酶抑制剂ASDO2/6 （类似物敏感的“DFG-out”激酶抑制剂2和6 ），其靶向 Cys-看门激酶的“DFG-out”构象亚微摩尔效力。我们在体外针对 Greatwall 激酶 (GWL)、Aurora-A 激酶和细胞周期蛋白依赖性激酶 1 以及使用表达 M110C-GWL 的小鼠胚胎成纤维细胞的细胞中验证了该系统。这些 Cys 守门激酶对ASDO2/6抑制敏感，但对 AS 激酶抑制剂 3MB-PP1 不敏感，反之亦然。这些化合物与AS激酶抑制剂一起，具有独立抑制多种AS激酶的潜力，可应用于系统水平和翻译激酶研究以及针对内源激酶的II型激酶抑制剂的合理设计。
更新日期：2018-09-21
中文翻译：
针对 Cys-Gatekeeper 激酶的 II 型激酶抑制剂与野生型和 Ala/Gly-Gatekeeper 激酶表现出正交性
类似物敏感（AS）激酶在看门位置含有大到小的突变，使得它们容易受到基于吡唑并嘧啶的Src激酶抑制剂的大类似物（例如PP1）的抑制。这种“凹凸孔”方法已用于 ∼520 种激酶中的至少 85 种，但许多激酶不耐受这种方法。为了扩展 AS 激酶技术的范围，我们设计了 II 型激酶抑制剂ASDO2/6 （类似物敏感的“DFG-out”激酶抑制剂2和6 ），其靶向 Cys-看门激酶的“DFG-out”构象亚微摩尔效力。我们在体外针对 Greatwall 激酶 (GWL)、Aurora-A 激酶和细胞周期蛋白依赖性激酶 1 以及使用表达 M110C-GWL 的小鼠胚胎成纤维细胞的细胞中验证了该系统。这些 Cys 守门激酶对ASDO2/6抑制敏感，但对 AS 激酶抑制剂 3MB-PP1 不敏感，反之亦然。这些化合物与AS激酶抑制剂一起，具有独立抑制多种AS激酶的潜力，可应用于系统水平和翻译激酶研究以及针对内源激酶的II型激酶抑制剂的合理设计。
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