Characterization of LY2228820 dimesylate, a potent and selective inhibitor of p38 MAPK with antitumor activity

Mol Cancer Ther. 2014 Feb;13(2):364-74. doi: 10.1158/1535-7163.MCT-13-0513. Epub 2013 Dec 19.


p38α mitogen-activated protein kinase (MAPK) is activated in cancer cells in response to environmental factors, oncogenic stress, radiation, and chemotherapy. p38α MAPK phosphorylates a number of substrates, including MAPKAP-K2 (MK2), and regulates the production of cytokines in the tumor microenvironment, such as TNF-α, interleukin-1β (IL-1β), IL-6, and CXCL8 (IL-8). p38α MAPK is highly expressed in human cancers and may play a role in tumor growth, invasion, metastasis, and drug resistance. LY2228820 dimesylate (hereafter LY2228820), a trisubstituted imidazole derivative, is a potent and selective, ATP-competitive inhibitor of the α- and β-isoforms of p38 MAPK in vitro (IC(50) = 5.3 and 3.2 nmol/L, respectively). In cell-based assays, LY2228820 potently and selectively inhibited phosphorylation of MK2 (Thr334) in anisomycin-stimulated HeLa cells (at 9.8 nmol/L by Western blot analysis) and anisomycin-induced mouse RAW264.7 macrophages (IC(50) = 35.3 nmol/L) with no changes in phosphorylation of p38α MAPK, JNK, ERK1/2, c-Jun, ATF2, or c-Myc ≤ 10 μmol/L. LY2228820 also reduced TNF-α secretion by lipopolysaccharide/IFN-γ-stimulated macrophages (IC(50) = 6.3 nmol/L). In mice transplanted with B16-F10 melanoma, tumor phospho-MK2 (p-MK2) was inhibited by LY2228820 in a dose-dependent manner [threshold effective dose (TED)(70) = 11.2 mg/kg]. Significant target inhibition (>40% reduction in p-MK2) was maintained for 4 to 8 hours following a single 10 mg/kg oral dose. LY2228820 produced significant tumor growth delay in multiple in vivo cancer models (melanoma, non-small cell lung cancer, ovarian, glioma, myeloma, breast). In summary, LY2228820 is a p38 MAPK inhibitor, which has been optimized for potency, selectivity, drug-like properties (such as oral bioavailability), and efficacy in animal models of human cancer.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenosine Triphosphate / metabolism
  • Animals
  • Anisomycin / pharmacology
  • Binding Sites
  • Blotting, Western
  • Cell Line
  • Cell Line, Tumor
  • Cells, Cultured
  • Cytokines / metabolism
  • Dose-Response Relationship, Drug
  • HeLa Cells
  • Humans
  • Imidazoles / chemistry
  • Imidazoles / pharmacology*
  • Macrophages / drug effects
  • Macrophages / metabolism
  • Melanoma, Experimental / drug therapy
  • Melanoma, Experimental / pathology
  • Mice
  • Molecular Structure
  • Neoplasms / drug therapy*
  • Neoplasms / genetics
  • Neoplasms / metabolism
  • Phosphorylation / drug effects
  • Pyridines / chemistry
  • Pyridines / pharmacology*
  • RNA Interference
  • Treatment Outcome
  • Xenograft Model Antitumor Assays*
  • p38 Mitogen-Activated Protein Kinases / antagonists & inhibitors*
  • p38 Mitogen-Activated Protein Kinases / genetics
  • p38 Mitogen-Activated Protein Kinases / metabolism


  • Cytokines
  • Imidazoles
  • Pyridines
  • Anisomycin
  • ralimetinib
  • Adenosine Triphosphate
  • p38 Mitogen-Activated Protein Kinases