Journal Article

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

Knapp, Stefan, Chaikuad, Apirat, Tarsounas, Madalena, Zimmer, Jutta, Gray, Nathanael S, M C Tacconi, Eliana, Liang, Yanke

2014

Overview

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.

• Publisher: Nature Publishing Group US,Nature Publishing Group
• Subject: 631/154/556 / 631/535/1266 / 631/67/1059 / 631/92/275 / Antineoplastic Agents - chemistry / Antineoplastic Agents - pharmacology / Binding Sites / Biochemical Engineering / Biochemistry / Bioorganic Chemistry / Cancer / Cell Biology / Cell Line, Tumor / Chemistry / Chemistry/Food Science / Enzyme Inhibitors - chemistry / Enzyme Inhibitors - pharmacology / Gene Expression / Gene Expression Regulation, Neoplastic / Humans / Indazoles - chemistry / Indazoles - pharmacology / Intracellular Signaling Peptides and Proteins - chemistry / Intracellular Signaling Peptides and Proteins - genetics / Intracellular Signaling Peptides and Proteins - metabolism / Kinetics / MAP Kinase Signaling System - drug effects / Mitogen-Activated Protein Kinase 1 - antagonists & inhibitors / Mitogen-Activated Protein Kinase 1 - chemistry / Mitogen-Activated Protein Kinase 1 - genetics / Mitogen-Activated Protein Kinase 1 - metabolism / Mitogen-Activated Protein Kinase 3 - antagonists & inhibitors / Mitogen-Activated Protein Kinase 3 - chemistry / Mitogen-Activated Protein Kinase 3 - genetics / Mitogen-Activated Protein Kinase 3 - metabolism / Mitogen-Activated Protein Kinase 8 - chemistry / Mitogen-Activated Protein Kinase 8 - genetics / Mitogen-Activated Protein Kinase 8 - metabolism / Pharmaceutical sciences / Piperazines - chemistry / Piperazines - pharmacology / Protein Binding / Protein Serine-Threonine Kinases - chemistry / Protein Serine-Threonine Kinases - genetics / Protein Serine-Threonine Kinases - metabolism / Protein Structure, Secondary / Protein Structure, Tertiary / Recombinant Proteins - chemistry / Recombinant Proteins - genetics / Recombinant Proteins - metabolism / Signal transduction / Upstream