A unique inhibitor binding site in ERK1/2 is associated with slow binding kinetics
- Nat Chem Biol. 2014 Oct;10(10):853-60. doi: 10.1038/nchembio.1629.
- 1. Structural Genomics Consortium, University of Oxford, Old Road Campus Research Building, Oxford, UK.
- 2. Telomere and Genome Stability Group, The Cancer Research UK and Medical Research Council Oxford Institute for Radiation Oncology, Old Road Campus Research Building, Oxford, UK.
- 3. Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Department of Cancer Biology, Dana Farber Cancer Institute, Boston, Massachusetts, USA.
- 4. 1] Structural Genomics Consortium, University of Oxford, Old Road Campus Research Building, Oxford, UK. [2] Department of Biochemistry and Molecular Medicine, George Washington University, Washington, DC, USA. [3] Target Discovery Institute, University of Oxford, Nuffield Department of Medicine Research Building, Oxford, UK.
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.