Structural determinants for ERK5 (MAPK7) and leucine rich repeat kinase 2 activities of benzo[e]pyrimido-[5,4-b]diazepine-6(11H)-ones.
Structural determinants for ERK5 (MAPK7) and leucine rich repeat kinase 2 activities of benzo[e]pyrimido-[5,4-b]diazepine-6(11H)-ones.
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DOI：
10.1016/j.ejmech.2013.10.052
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发表时间：
2013
影响因子：
6.7
通讯作者：
Gray, Nathanael S.
中科院分区：
文献类型：
--
作者：
Deng, Xianming;Elkins, Jonathan M.;Zhang, Jinwei;Yang, Qingkai;Erazo, Tatiana;Gomez, Nestor;Choi, Hwan Geun;Wang, Jinhua;Dzamko, Nicolas;Lee, Jiing-Dwan;Sim, Taebo;Kim, NamDoo;Alessi, Dario R.;Lizcano, Jose M.;Knapp, Stefan;Gray, Nathanael S.
苯并[e]嘧啶基-[5,4-b]二氮杂卓-6(11H)-one核心先前被发现是一种新型ERK5（也称为MAPK7和BMK1）抑制剂支架。对该支架的进一步结构-活性关系研究发现 ERK5-IN-1 (26) 是迄今为止报道的最具选择性和最有效的 ERK5 抑制剂。 26 有效抑制 ERK5 生化作用，IC50 为 0.162 ± 0.006 μM，在细胞中抑制表皮生长因子诱导的 ERK5 自磷酸化的 EC50 为 0.09 ± 0.03 μM。此外，26 比其他激酶表现出优异的选择性，KINOMEscan 选择性评分 (S10) 为 0.007，并且在小鼠中表现出 90% 的出色生物利用度 (F%)。 26 将作为研究 ERK5 信号通路的有价值的工具化合物，并作为开发 ERK5 定向治疗剂的起点。 ERK5 苯并[e]嘧啶基-[5,4-b]二氮杂卓-6(11H)-酮的结构决定因素。高选择性 ERK5 抑制剂，在体外和体内均具有良好的疗效。代表了开发 ERK5 定向治疗剂的良好模板。
The benzo[e]pyrimido-[5,4-b]diazepine-6(11H)-one core was discovered as a novel ERK5 (also known as MAPK7 and BMK1) inhibitor scaffold, previously. Further structure–activity relationship studies of this scaffold led to the discovery of ERK5-IN-1 (26) as the most selective and potent ERK5 inhibitor reported to date. 26 potently inhibits ERK5 biochemically with an IC50 of 0.162 ± 0.006 μM and in cells with a cellular EC50 for inhibiting epidermal growth factor induced ERK5 autophosphorylation of 0.09 ± 0.03 μM. Furthermore, 26 displays excellent selectivity over other kinases with a KINOMEscan selectivity score (S10) of 0.007, and exhibits exceptional bioavailability (F%) of 90% in mice. 26 will serve as a valuable tool compound to investigate the ERK5 signaling pathway and as a starting point for developing an ERK5 directed therapeutic agent. Structural determinants of benzo[e]pyrimido-[5,4-b]diazepine-6(11H)-ones for ERK5. Highly selective ERK5 inhibitor with good efficacy both in vitro and in vivo. Represents a good template for developing ERK5 directed therapeutic agent.
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作者：
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