title: E6201 [(3S,4R,5Z,8S,9S,11E)-14-(ethylamino)-8, 9,16-trihydroxy-3,4-dimethyl-3,4,9,19-tetrahydro-1H-2-benzoxacyclotetradecine-1,7(8H)-dione], a novel kinase inhibitor of mitogen-activated protein kinase/extracellular signal-regulated kinase kinase (MEK)-1 and MEK kinase-1: in vitro characterization of its anti-inflammatory and antihyperproliferative activities.
abstract: The goal of this study is to identify a novel inhibitor with anti-inflammatory and antiproliferative properties for the treatment of psoriasis. Compound f152A1 [(3S,5Z,8S,11E)-8,9,16-trihydroxy-14-methoxy-3-methyl-3,4,9,10-tetrahydro-1H-benzo[c][1]oxacyclotetradecine1,7(8H)-dione] was identified as the main active metabolite with strong inhibitory activity against tumor necrosis factor-alpha (TNFalpha) transcription in a fraction originated from the fermentation broth of the fungus Curvularia verruculosa. Although active in cell-based assays, f152A1 was unstable in plasma and liver microsome preparations, thus limiting its pharmaceutical utilization. To improve the metabolic properties of f152A1, a medicinal chemistry program was undertaken, resulting in the generation of over 400 analogs of f152A1. Eventually, E6201 [(3S,4R,5Z,8S,9S,11E)-14-(ethylamino)-8,9,16-trihydroxy-3,4-dimethyl-3,4,9,19-tetrahydro-1H-2-benzoxacyclotetradecine-1,7(8H)-dione] was identified as a promising analog in this series. In the present study, we characterized the in vitro activities of E6201 and discovered that the compound inhibits lipopolysaccharide-activated TNFalpha reporter activity in THP-1-33 cells with an IC(50) value of 50 nM and selectively inhibits mitogen-activated protein kinase/extracellular signal-regulated kinase kinase (MEK)-1 and MEK kinase-1 in cell-free biochemical assays. In addition, E6201 showed inhibitory activity in several other cell-based systems: 1) phosphorylation of c-jun N-terminal kinase and p38 MAPKs; 2) nuclear factor-kappaB and activated protein-1 activation in various cell types; 3) interleukin (IL)-2 production from human lymphocytes; 4) hyperproliferation of human keratinocytes; 5) IL-8 production from human keratinocytes; and 6) proinflammatory cytokine production from human peripheral blood mononuclear cells. Based on the data presented here, E6201 may be beneficial for treatment of inflammatory and hyperproliferative diseases such as psoriasis through its anti-inflammatory activities on immune cells and antihyperproliferative activities on keratinocytes.
authors.affiliation: Eisai Tsukuba Research Laboratories, Ibaraki, Japan. m4-goto@hhc.eisai.co.jp
authors.forename: Masaki
authors.initials: M
authors.lastname: Goto
authors.forename: Jesse
authors.initials: J
authors.lastname: Chow
authors.forename: Kenzo
authors.initials: K
authors.lastname: Muramoto
authors.forename: Ken-ichi
authors.initials: K
authors.lastname: Chiba
authors.forename: Satoshi
authors.initials: S
authors.lastname: Yamamoto
authors.forename: Masanori
authors.initials: M
authors.lastname: Fujita
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Obaishi
authors.forename: Kenji
authors.initials: K
authors.lastname: Tai
authors.forename: Yoshiharu
authors.initials: Y
authors.lastname: Mizui
authors.forename: Isao
authors.initials: I
authors.lastname: Tanaka
authors.forename: Donna
authors.initials: D
authors.lastname: Young
authors.forename: Hua
authors.initials: H
authors.lastname: Yang
authors.forename: Yuan J
authors.initials: YJ
authors.lastname: Wang
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Shirota
authors.forename: Fabian
authors.initials: F
authors.lastname: Gusovsky
mesh_terms: D000199:Actins / Q000378:metabolism; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects*; D016207:Cytokines / Q000096:biosynthesis; D006801:Humans; D007111:Immunity, Cellular / Q000187:drug effects; D007202:Indicators and Reagents; D007376:Interleukin-2 / Q000096:biosynthesis; D016209:Interleukin-8 / Q000096:biosynthesis; D019169:Jurkat Cells; D015603:Keratinocytes / Q000187:drug effects; D007783:Lactones / Q000494:pharmacology*; D008214:Lymphocytes / Q000187:drug effects; D048369:MAP Kinase Kinase 1 / Q000037:antagonists & inhibitors*; D048728:MAP Kinase Kinase Kinase 1 / Q000037:antagonists & inhibitors*; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors*; D010766:Phosphorylation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: C545120:14-(ethylamino)-8,9,16-trihydroxy-3,4-dimethyl-3,4,9,19-tetrahydro-1H-2-benzoxacyclotetradecine-1,7(8H)-dione; D000199:Actins; D000893:Anti-Inflammatory Agents; D016207:Cytokines; D007202:Indicators and Reagents; D007376:Interleukin-2; D016209:Interleukin-8; C118715:LL Z1640-2; D007783:Lactones; D047428:Protein Kinase Inhibitors; D014409:Tumor Necrosis Factor-alpha; D011505:Protein-Tyrosine Kinases; D020928:Mitogen-Activated Protein Kinases; D048728:MAP Kinase Kinase Kinase 1; D048369:MAP Kinase Kinase 1; C482125:MAP2K1 protein, human