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Development of Inhibitors of Protein-protein Interactions through REPLACE: Application to the Design and Development Non-ATP Competitive CDK Inhibitors
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A unique inhibitor binding site in ERK1/2 is associated with slow binding kinetics

Apirat Chaikuad1, Eliana M C Tacconi2, Jutta Zimmer2

  • 1Structural Genomics Consortium, University of Oxford, Old Road Campus Research Building, Oxford, UK.

Nature Chemical Biology
|September 8, 2014
PubMed

Insights

SCH772984 is a potent ERK1/2 inhibitor. Its unique binding to ERK1/2, distinct from off-targets, creates a novel pocket, enabling the design of specific kinase inhibitors with prolonged activity.

Area of Science:

  • Biochemistry
  • Molecular Biology
  • Drug Discovery

Background:

  • The Extracellular signal-Regulated Kinase (ERK) pathway is crucial in cancer development.
  • Targeting upstream signaling molecules has yielded successful cancer therapies.
  • SCH772984 is a recently identified selective and potent inhibitor of ERK1/2.

Purpose of the Study:

  • To elucidate the structural mechanism behind SCH772984's selectivity for ERK1/2.
  • To understand the distinct binding modes of SCH772984 with ERK1/2 versus off-target kinases.
  • To explore the implications of SCH772984's binding kinetics for inhibitor design.

Main Methods:

  • X-ray crystallography was used to determine the structures of SCH772984 bound to ERK1/2, haspin, and JNK1.
  • In vitro and cell-based assays were employed to assess binding kinetics.
  • Comparative structural analysis was performed to identify differences in binding modes.

Main Results:

  • SCH772984 induces a unique binding pocket in ERK1/2, involving an inactive phosphate-binding loop and a tilted helix αC.
  • Binding to off-target kinases haspin and JNK1 occurs via canonical type I modes.
  • The novel ERK1/2 binding mode is associated with slow binding kinetics.
  • This unique interaction was observed in both in vitro and cellular assays.

Conclusions:

  • The structural mechanism explains SCH772984's high selectivity for ERK1/2.
  • The distinct binding mode and slow kinetics offer a template for designing next-generation kinase inhibitors.
  • This approach could lead to more specific and durable on-target activity for cancer therapeutics.

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