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Related Experiment Video

Updated: Feb 26, 2026

Development of Inhibitors of Protein-protein Interactions through REPLACE: Application to the Design and Development Non-ATP Competitive CDK Inhibitors
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Structure-Guided Strategy for the Development of Potent Bivalent ERK Inhibitors.

Bernhard C Lechtenberg1, Peter D Mace1, E Hampton Sessions2

  • 1Cancer Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, California 92037, United States.

ACS Medicinal Chemistry Letters
|July 26, 2017
PubMed
Summary

Researchers developed novel bivalent ERK inhibitors by combining small molecules with peptides targeting the D-site recruitment site (DRS). The lead compound SBP3 shows enhanced potency against ERK, a key target in cancer drug resistance.

Keywords:
MAPKcancerclick chemistryinhibitormelanomapeptidestructure-based drug design

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Protein WISDOM: A Workbench for In silico De novo Design of BioMolecules
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Area of Science:

  • Oncology
  • Molecular Biology
  • Drug Discovery

Background:

  • The RAS-RAF-MEK-ERK signaling pathway drives cancer cell growth and malignancy.
  • Drug resistance to RAF or MEK inhibitors is a significant clinical challenge, often involving ERK reactivation.
  • ERK remains a critical target for developing new anti-cancer therapies.

Purpose of the Study:

  • To design and characterize novel bivalent inhibitors targeting the Extracellular signal-Regulated Kinase (ERK).
  • To investigate the potential of combining ATP-binding pocket inhibitors with peptides targeting the D-site recruitment site (DRS).
  • To evaluate the potency and specificity of these novel bivalent inhibitors.

Main Methods:

  • Design of bivalent inhibitors using click chemistry, linking small molecule ATP-binding inhibitors with ERK-targeting peptides.
  • Structural and functional characterization of bivalent inhibitors, including potency and specificity assays.
  • Assessment of inhibitor binding to ERK and related kinases, including those with a DRS.

Main Results:

  • The lead bivalent inhibitor, SBP3, demonstrated significantly improved potency compared to the small molecule inhibitor alone.
  • SBP3 exhibited binding to several ERK-related kinases possessing a DRS, underscoring the need for specificity verification.
  • SBP3 did not inhibit other kinases within the CMGC branch, indicating some selectivity.

Conclusions:

  • Bivalent inhibitors combining ATP-site and DRS-targeting elements represent a promising strategy for overcoming ERK-mediated drug resistance.
  • The modular design allows for versatile combinations of inhibitors and peptides for tailored therapeutic approaches.
  • Experimental validation of specificity is crucial for bivalent inhibitor development due to potential off-target interactions with related kinases.