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• W2025808353 abstract "p38α mitogen-activated protein kinase (MAPK) is activated by cancer cells in response to environmental factors, such as oncogenic stress, radiation, and chemotherapy. p38α MAPK phosphorylates a number of substrates, including MAPKAP-K2 (MK2), and regulates the production/message stability of cytokines produced in the tumor microenvironment, such as TNFα, IL1 β, IL-6 and IL-8. p38α MAPK is activated and highly expressed in human cancers and may play a role in tumor growth, invasion and metastasis. LY2228820 dimesylate is a tri-substituted imidazole derivative that is a potent and ATP-competitive inhibitor of the α and β isoforms of p38 MAPK in vitro (IC50 = 5.3 nM and 3.2 nM, respectively). This compound displays > 1000-fold selectivity for p38α MAPK versus 179 other kinases tested (including p38δ and γ isoforms). In cell-based assays, LY2228820 dimesylate also potently and selectively inhibits phosphorylation of MK2 (Thr334) in TNFα-stimulated HeLa cells (IC50 = 8.1 nM) and anisomycin-induced mouse RAW264.7 macrophages (IC50 = 35.3 nM) with no changes in phosphorylation of p38α MAPK, JNK, ERK1/2, c-jun, ATF2 or cMyc at concentrations up to 10μM. LY2228820 dimesylate also reduces TNFα secretion by LPS/IFNγ-stimulated macrophages (IC50 = 6.3 nM). In mice transplanted with B16-F10 melanomas, phospho-MK2 was effectively inhibited by LY2228820 dimesylate in tumors in a dose-dependent manner (TMED70 = 19.4 mg/kg). Significant target inhibition (>40% inhibition of phospho-MK2) was maintained for approx. 4–8hrs following a single 10mg/kg oral dose. In a broad range of xenograft models (A-549 NSCLC, SK-OV-3 Ovarian, U-87MG Glioma, MDA-MB-468 Breast), LY2228820 dimesylate demonstrates significant tumor growth delay. In summary, LY2228820 dimesylate is a novel, potent and selective inhibitor of p38 MAPK with anti-tumor activity. Further studies are ongoing to determine its molecular mechanism(s) of action, potential for combination with standard-of-care agents, and potential clinical activity. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr B235." @default.
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• W2025808353 date "2011-11-12" @default.
• W2025808353 modified "2023-09-26" @default.
• W2025808353 title "Abstract B235: Characterization of LY2228820 dimesylate, a potent and selective inhibitor of p38 MAPK with antitumor activity." @default.
• W2025808353 doi "https://doi.org/10.1158/1535-7163.targ-11-b235" @default.
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