Lin Emme C K, Amantea Christopher M, Nomanbhoy Tyzoon K, Weissig Helge, Ishiyama Junichi, Hu Yi, Sidique Shyama, Li Bei, Kozarich John W, Rosenblum Jonathan S
ActivX Biosciences, Inc., La Jolla, CA 92037;
ActivX Biosciences, Inc., La Jolla, CA 92037.
Proc Natl Acad Sci U S A. 2016 Oct 18;113(42):11865-11870. doi: 10.1073/pnas.1609019113. Epub 2016 Sep 27.
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.
与丝裂原活化蛋白激酶（MAPK）家族的其他成员不同，细胞外信号调节激酶5（ERK5）除了具有一个N端的典型激酶结构域外，还含有一个具有转录激活能力的大的C端结构域。ERK5的基因缺失会导致胚胎致死，组织特异性缺失对红细胞生成、心脏功能和神经发生有深远影响。此外，ERK5的缺失具有抗炎和抗肿瘤作用。在炎症和肿瘤学的细胞及动物模型中，小分子抑制ERK5已显示出有前景的活性。在此，我们报告强效、选择性ERK5抑制剂的合成及生物学特性。与ERK5的基因缺失/敲除以及用先前报道的化合物进行抑制不同，用新的抑制剂中选择性最强的抑制剂抑制该激酶没有抗炎或抗增殖活性。先前报道的ERK5抑制剂的疗效来源显示为对溴结构域的脱靶活性，溴结构域是在转录过程中参与识别乙酰赖氨酸残基的保守蛋白模块。ERK5基因缺失或敲除所报道的表型可能源于ERK5非催化功能的去除。新报道的抑制剂应有助于确定众多报道的表型中哪些是由激酶活性引起的，并明确哪些可以进行药理靶向。
