AX-15836是有效，选择性的ERK5抑制剂，IC50值为8nM。
AX-15836 is a potent and selective ERK5 inhibitor with an IC50 of 8 nM.
AX-15836 shows more than 1,000-fold selectivity for ERK5 over a panel of over 200 kinases. It also exhibits selectivity over BRD4 with a Kd of 3,600 nM. AX15836 shows similar intracellular potency (4-9 nM) across all cells tested, including peripheral blood mononuclear cells (PBMCs), endothelial cells, and oncogenic cell lines. AX15836 was completely ineffective (EC50>10 μM) to suppress inflammatory cytokine response, suggesting that it was the BRD inhibition component of the compounds that mediated cytokine reduction. In HUVEC and HeLa cell types, samples treated with AX15836 shows very few genes to be differentially expressed. AX15836 could clearly inhibit the EGF-stimulated, phosphorylated form of ERK5 in HeLa cells[1].
[1]. Lin EC, et al. ERK5 kinase activity is dispensable for cellular immune response and proliferation. Proc Natl Acad Sci U S A. 2016 Oct 18;113(42):11865-11870.
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Cell experiment: |
For proliferation studies, cells are treated with eight-point serial dilution series of AX-15836 (starting concentration of 15 μM) or with DMSO vehicle (0.25% final volume). For MM.1S cells, compound was added 1 h before adding recombinant human IL-6 at 5 nM. After 3 d, the relative number of viable cells was measured via quantitation of ATP using CellTiter-Glo 2.0 reagent. Luminescence was read on the Synergy 2 multimode reader[1]. |
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参考文献: [1]. Lin EC, et al. ERK5 kinase activity is dispensable for cellular immune response and proliferation. Proc Natl Acad Sci U S A. 2016 Oct 18;113(42):11865-11870. |
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