Identification of a selective ERK inhibitor and structural determination of the inhibitor–ERK2 complex

• DOI: 10.1016/j.bbrc.2005.08.082
• Publication Date: 2005-08-23T18:13:13Z
• Authors: Makoto Ohori; Takayoshi Kinoshita; Mitsuru Okubo; Kentaro Sato; Akiko Yamazaki; Hiroyuki Arakawa; Shintaro Nishimura; Noriaki Inamura; Hidenori Nakajima; Masahiro Neya; Hiroshi Miyake; Takashi Fujii
• Keywords: Mitogen-Activated Protein Kinase 1; Models, Molecular; 0301 basic medicine; Mitogen-Activated Protein Kinase 3; Molecular Structure; Sequence Homology, Amino Acid; Molecular Sequence Data; Crystallography, X-Ray; Cell Line; Substrate Specificity; 3. Good health; Pyridazines; 03 medical and health sciences; Mink; Animals; Pyrazoles; Amino Acid Sequence; Enzyme Inhibitors

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.