title: Identification of a selective ERK inhibitor and structural determination of the inhibitor-ERK2 complex.
abstract: Selective inhibition of extracellular signal-regulated kinase (ERK) represents a potential approach for the treatment of cancer and other diseases; however, no selective inhibitors are currently available. Here, we describe an ERK-selective inhibitor, FR180204, and determine the structural basis of its selectivity. FR180204 inhibited the kinase activity of ERK1 and ERK2, with K(i) values 0.31 and 0.14microM, respectively. Lineweaver-Burk analysis of the binding interaction revealed that FR180204 acted as competitive inhibitor of ATP. In mink lung epithelial Mv1Lu cells, FR180204 inhibited TGFbeta-induced luciferase-expression. X-ray crystal structure analysis of the human ERK2/FR180204 complex revealed that Q105, D106, L156, and C166, which form the ATP-binding pocket on ERK, play important roles in the drug/protein interaction. These results suggest that FR180204 is an ERK-selective and cell-permeable inhibitor, and could be useful for elucidating the roles of ERK as well as for drug development.
authors.affiliation: Lead Discovery Research Laboratories, Astellas Pharma Inc., Miyukigaoka 21, Tsukuba, Ibaraki 305-8585, Japan. makoto.ohori@jp.astellas.com
authors.forename: Makoto
authors.initials: M
authors.lastname: Ohori
authors.forename: Takayoshi
authors.initials: T
authors.lastname: Kinoshita
authors.forename: Mitsuru
authors.initials: M
authors.lastname: Okubo
authors.forename: Kentaro
authors.initials: K
authors.lastname: Sato
authors.forename: Akiko
authors.initials: A
authors.lastname: Yamazaki
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Arakawa
authors.forename: Shintaro
authors.initials: S
authors.lastname: Nishimura
authors.forename: Noriaki
authors.initials: N
authors.lastname: Inamura
authors.forename: Hidenori
authors.initials: H
authors.lastname: Nakajima
authors.forename: Masahiro
authors.initials: M
authors.lastname: Neya
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Miyake
authors.forename: Takashi
authors.initials: T
authors.lastname: Fujii
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D002460:Cell Line; D018360:Crystallography, X-Ray; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D008907:Mink; D019950:Mitogen-Activated Protein Kinase 1 / Q000037:antagonists & inhibitors* / Q000737:chemistry; D048052:Mitogen-Activated Protein Kinase 3 / Q000037:antagonists & inhibitors*; D008958:Models, Molecular; D008969:Molecular Sequence Data; D015394:Molecular Structure; D011720:Pyrazoles / Q000737:chemistry / Q000494:pharmacology*; D011724:Pyridazines / Q000737:chemistry / Q000494:pharmacology*; D017386:Sequence Homology, Amino Acid; D013379:Substrate Specificity
chemical_list: D004791:Enzyme Inhibitors; C505241:FR 180204; D011720:Pyrazoles; D011724:Pyridazines; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3