1. Academic Validation
  2. Characterization of LY2228820 dimesylate, a potent and selective inhibitor of p38 MAPK with antitumor activity

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.
Robert M Campbell 1 Bryan D Anderson Nathan A Brooks Harold B Brooks Edward M Chan Alfonso De Dios Raymond Gilmour Jeremy R Graff Enrique Jambrina Mary Mader Denis McCann Songqing Na Stephen H Parsons Susan E Pratt Chuan Shih Louis F Stancato James J Starling Courtney Tate Juan A Velasco Yong Wang Xiang S Ye
Affiliations

Affiliation

  • 1 Corresponding Author: Robert M. Campbell, Eli Lilly and Company, Lilly Corporate Center, dc0424, Indianapolis, IN 46285. campbell_robert_morris@lilly.com.
Abstract

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.

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