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• W2078902726 abstract "Crystallographic analysis depicting the interaction of the kinase inhibitor SCH772984 with ERK1/2 reveals a unique binding pocket distinct from off-targets such as haspin and is associated with slow binding kinetics and prolonged inhibitory activity. 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." @default.
• W2078902726 created "2016-06-24" @default.
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• W2078902726 date "2014-09-07" @default.
• W2078902726 modified "2023-10-11" @default.
• W2078902726 title "A unique inhibitor binding site in ERK1/2 is associated with slow binding kinetics" @default.
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• W2078902726 doi "https://doi.org/10.1038/nchembio.1629" @default.
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• W2078902726 hasPublicationYear "2014" @default.
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