1. Academic Validation
  2. Identification of a selective ERK inhibitor and structural determination of the inhibitor-ERK2 complex

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

  • Biochem Biophys Res Commun. 2005 Oct 14;336(1):357-63. doi: 10.1016/j.bbrc.2005.08.082.
Makoto Ohori 1 Takayoshi Kinoshita Mitsuru Okubo Kentaro Sato Akiko Yamazaki Hiroyuki Arakawa Shintaro Nishimura Noriaki Inamura Hidenori Nakajima Masahiro Neya Hiroshi Miyake Takashi Fujii
Affiliations

Affiliation

  • 1 Lead Discovery Research Laboratories, Astellas Pharma Inc., Miyukigaoka 21, Tsukuba, Ibaraki 305-8585, Japan. makoto.ohori@jp.astellas.com
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.

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