ERK5 kinase activity is dispensable for cellular immune response and proliferation
ERK5 kinase activity is dispensable for cellular immune response and proliferation
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DOI：
10.1073/pnas.1609019113
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发表时间：
2016-10-18
影响因子：
11.1
通讯作者：
Rosenblum, Jonathan S.
中科院分区：
文献类型：
--
作者：
Lin, Emme C. K.;Amantea, Christopher M.;Rosenblum, Jonathan S.
与MAPK家族的其他成员不同，ERK5含有一个大的具有转录激活能力的C末端结构域，此外还有一个N末端的规范激活域。ERK5的基因缺失是胚胎致死的，组织限制性缺失对红系发育、心脏功能和神经发生有深远的影响。此外，ERK5的缺失具有抗炎和抗肿瘤的作用。小分子抑制ERK5已被证明在炎症和肿瘤学的细胞和动物模型中具有良好的活性。在这里，我们报告了有效的，选择性的ERK5抑制剂的合成和生物学特性。与ERK5的基因缺失/缺失和先前报道的化合物抑制相反，用最具选择性的新抑制剂抑制该激酶没有抗炎或抗增殖活性。以前报道的ERK5抑制剂的有效来源是溴域上的非靶点活性，这些保守的蛋白质模块参与了转录过程中识别乙酰赖氨酸残基的过程。报告的ERK5基因缺失或缺失的表型很可能是由于ERK5的非催化功能被移除。新报道的抑制剂应该有助于确定许多报道的表型中哪些是由于激酶活性所致，并勾画出哪些可以作为药理靶点。
Unlike other members of the MAPK family, ERK5 contains a large C-terminal domain with transcriptional activation capability in addition to an N-terminal canonical kinase domain. Genetic deletion of ERK5 is embryonic lethal, and tissue-restricted deletions have profound effects on erythroid development, cardiac function, and neurogenesis. In addition, depletion of ERK5 is antiinflammatory and antitumorigenic. Small molecule inhibition of ERK5 has been shown to have promising activity in cell and animal models of inflammation and oncology. Here we report the synthesis and biological characterization of potent, selective ERK5 inhibitors. In contrast to both genetic depletion/deletion of ERK5 and inhibition with previously reported compounds, inhibition of the kinase with the most selective of the new inhibitors had no antiinflammatory or antiproliferative activity. The source of efficacy in previously reported ERK5 inhibitors is shown to be off-target activity on bromodomains, conserved protein modules involved in recognition of acetyl-lysine residues during transcriptional processes. It is likely that phenotypes reported from genetic deletion or depletion of ERK5 arise from removal of a noncatalytic function of ERK5. The newly reported inhibitors should be useful in determining which of the many reported phenotypes are due to kinase activity and delineate which can be pharmacologically targeted.