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.
Nat Chem Biol
853 - 860
Antineoplastic Agents, Binding Sites, Cell Line, Tumor, Enzyme Inhibitors, Gene Expression, Gene Expression Regulation, Neoplastic, Humans, Indazoles, Intracellular Signaling Peptides and Proteins, Kinetics, MAP Kinase Signaling System, Mitogen-Activated Protein Kinase 1, Mitogen-Activated Protein Kinase 3, Mitogen-Activated Protein Kinase 8, Piperazines, Protein Binding, Protein Structure, Secondary, Protein Structure, Tertiary, Protein-Serine-Threonine Kinases, Recombinant Proteins