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Cited by 121Melanoma and MAPK PathwaysProtein Kinase Regulation and GTPase SignalingProtein Tyrosine Phosphatases

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Characterization of LY2228820 Dimesylate, a Potent and Selective Inhibitor of p38 MAPK with Antitumor Activity

Campbell, Robert M., Anderson, Bryan D., Brooks, Nathan A., Brooks, Harold B., Chan, Edward M., De Dios, Alfonso, Gilmour, Raymond, Graff, Jeremy R., Jambrina, Enrique, Mader, Mary, McCann, Denis, Na, Songqing, Parsons, Stephen H., Pratt, Susan E., Shih, Chuan, Stancato, Louis F., Starling, James J., Tate, Courtney, Velasco, Juan A., Wang, Yong, Ye, Xiang S.·2014·Molecular Cancer Therapeutics
DOI 10.1158/1535-7163.mct-13-0513

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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 (IC50 = 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 (IC50 = 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 (IC50 = 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. Mol Cancer Ther; 13(2); 364–74. ©2013 AACR.

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Metadata

Authors
Campbell, R. M., Anderson, B. D., Brooks, N. A., Brooks, H. B., Chan, E. M., De Dios, A., Gilmour, R., Graff, J. R., Jambrina, E., Mader, M., McCann, D., Na, S., Parsons, S. H., Pratt, S. E., Shih, C., Stancato, L. F., Starling, J. J., Tate, C., Velasco, J. A., Wang, Y., & Ye, X. S.
Affiliations
Eli Lilly (United States) (US)
ORCID
Venue
Molecular Cancer Therapeutics
Publisher
American Association for Cancer Research (AACR)
Published
2014-02-01
Volume
13
Issue
2
Pages
364-374
ISSN
  • 1535-7163 (ISSN-L)
  • 1538-8514
DOI
10.1158/1535-7163.mct-13-0513
OpenAlex
W2112436968
Cited by
121
References
2
Citations by year
2026: 2 · 2025: 6 · 2024: 8 · 2023: 8 · 2022: 8 · 2021: 6 · 2020: 26 · 2019: 18 · 2018: 12 · 2017: 5 · 2016: 8 · 2015: 13 · 2014: 1
FWCI
2.42
Type
journal article
Language
en
Open access
closed
Locations
  • Molecular Cancer Therapeutics (publishedVersion)
  • PubMed (publishedVersion)
Funders
Eli Lilly and Company
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Melanoma and MAPK Pathways
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Tyrosine Phosphatases
Keywords
p38 MAPK inhibitor, p38α MAPK, anticancer activity, melanoma, non-small cell lung cancer, ovarian cancer, tumor growth inhibition, TNF-alpha secretion, macrophages, drug resistance, imidazole derivatives, tumor microenvironment
MeSH terms
Adenosine Triphosphate, Animals, Anisomycin, Binding Sites, Cell Line, Cells, Cultured, Dose-Response Relationship, Drug, HeLa Cells, Humans, Imidazoles, Macrophages, Melanoma, Experimental, Neoplasms, Phosphorylation, Pyridines, Blotting, Western, Molecular Structure, Cytokines, Treatment Outcome, Xenograft Model Antitumor Assays, RNA Interference, Cell Line, Tumor, p38 Mitogen-Activated Protein Kinases, Mice

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