A unique inhibitor binding site in ERK1/2 is associated with slow binding kinetics.

Journal article

Activation of the ERK pathway is a hallmark of cancer, and targeting of upstream signaling partners led to the development of approved drugs. Recently, SCH772984 has been shown to be a selective and potent ERK1/2 inhibitor. Here we report the structural mechanism for its remarkable selectivity. In ERK1/2, SCH772984 induces a so-far-unknown binding pocket that accommodates the piperazine-phenyl-pyrimidine decoration. This new binding pocket was created by an inactive conformation of the phosphate-binding loop and an outward tilt of helix αC. In contrast, structure determination of SCH772984 with the off-target haspin and JNK1 revealed two canonical but distinct type I binding modes. Notably, the new binding mode with ERK1/2 was associated with slow binding kinetics in vitro as well as in cell-based assay systems. The described binding mode of SCH772984 with ERK1/2 enables the design of a new type of specific kinase inhibitors with prolonged on-target activity.

Authors: Chaikuad, A; Tacconi, E; Zimmer, J; Liang, Y; Gray, N

• Publication status: Published
• Journal: Nature chemical biology
• Volume: 10
• Issue: 10
• Pages: 853-860
• Publication date: 2014-10-01
• DOI: 10.1038/nchembio.1629
• EISSN: 1552-4469
• ISSN: 1552-4450
• Language: English
• Keywords: Mitogen-Activated Protein Kinase 1; Piperazines; Binding Sites; Gene Expression; Enzyme Inhibitors; Mitogen-Activated Protein Kinase 8; Protein Structure, Tertiary; Protein Binding; Kinetics; Recombinant Proteins; Antineoplastic Agents; Mitogen-Activated Protein Kinase 3; Cell Line, Tumor; Protein Structure, Secondary; Intracellular Signaling Peptides and Proteins; Humans; Protein-Serine-Threonine Kinases; MAP Kinase Signaling System; Gene Expression Regulation, Neoplastic; Indazoles