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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

Makoto Ohori, Takayoshi Kinoshita, Mitsuru Okubo, Kentaro Sato, Akiko Yamazaki, Hiroyuki Arakawa, Shintaro Nishimura, Noriaki Inamura, Hidenori Nakajima, Masahiro Neya, Hiroshi Miyake, Takashi Fujii

Biochem Biophys Res Commun. 2005 Oct 14;336(1):357-63.

PMID: 16139248

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.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
AP865362749-B	FR180204		865362-74-9	Price

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