title: Characterization of LY2228820 dimesylate, a potent and selective inhibitor of p38 MAPK with antitumor activity.
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.
authors.affiliation: Corresponding Author: Robert M. Campbell, Eli Lilly and Company, Lilly Corporate Center, dc0424, Indianapolis, IN 46285. campbell_robert_morris@lilly.com.
authors.forename: Robert M
authors.initials: RM
authors.lastname: Campbell
authors.forename: Bryan D
authors.initials: BD
authors.lastname: Anderson
authors.forename: Nathan A
authors.initials: NA
authors.lastname: Brooks
authors.forename: Harold B
authors.initials: HB
authors.lastname: Brooks
authors.forename: Edward M
authors.initials: EM
authors.lastname: Chan
authors.forename: Alfonso
authors.initials: A
authors.lastname: De Dios
authors.forename: Raymond
authors.initials: R
authors.lastname: Gilmour
authors.forename: Jeremy R
authors.initials: JR
authors.lastname: Graff
authors.forename: Enrique
authors.initials: E
authors.lastname: Jambrina
authors.forename: Mary
authors.initials: M
authors.lastname: Mader
authors.forename: Denis
authors.initials: D
authors.lastname: McCann
authors.forename: Songqing
authors.initials: S
authors.lastname: Na
authors.forename: Stephen H
authors.initials: SH
authors.lastname: Parsons
authors.forename: Susan E
authors.initials: SE
authors.lastname: Pratt
authors.forename: Chuan
authors.initials: C
authors.lastname: Shih
authors.forename: Louis F
authors.initials: LF
authors.lastname: Stancato
authors.forename: James J
authors.initials: JJ
authors.lastname: Starling
authors.forename: Courtney
authors.initials: C
authors.lastname: Tate
authors.forename: Juan A
authors.initials: JA
authors.lastname: Velasco
authors.forename: Yong
authors.initials: Y
authors.lastname: Wang
authors.forename: Xiang S
authors.initials: XS
authors.lastname: Ye
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D000841:Anisomycin / Q000494:pharmacology; D001665:Binding Sites; D015153:Blotting, Western; D002460:Cell Line; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D016207:Cytokines / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D006367:HeLa Cells; D006801:Humans; D007093:Imidazoles / Q000737:chemistry / Q000494:pharmacology*; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism; D008546:Melanoma, Experimental / Q000188:drug therapy / Q000473:pathology; D051379:Mice; D015394:Molecular Structure; D009369:Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D011725:Pyridines / Q000737:chemistry / Q000494:pharmacology*; D034622:RNA Interference; D016896:Treatment Outcome; D023041:Xenograft Model Antitumor Assays; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism
chemical_list: D016207:Cytokines; D007093:Imidazoles; D011725:Pyridines; D000841:Anisomycin; C580958:ralimetinib; D000255:Adenosine Triphosphate; D048051:p38 Mitogen-Activated Protein Kinases