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Related Concept Videos

The Ras Gene02:38

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The Ras-gene-encoded proteins are regulators of signaling pathways controlling cell proliferation, differentiation, or cell survival. The Ras-gene family in humans constitutes three primary members—the HRas, NRas, and KRas. These genes code for four functionally distinct yet closely related proteins—the HRas, NRas, KRas4A, and KRas4B. The involvement of mutant Ras genes in human cancer was first discovered in 1982 and is among the most common causes of human tumorigenesis.
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Related Experiment Video

Updated: May 21, 2025

High-Throughput Cellular Profiling of Targeted Protein Degradation Compounds Using HiBiT CRISPR Cell Lines
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Reengineering of a Proteomimetic Pan-Ras Inhibitor into a Ras Degrader.

Joseph F Ongkingco1, Seong Ho Hong1, Eugene D Toth1

  • 1Department of Chemistry, New York University, 100 Washington Square East, New York, NY, 10003, USA.

Angewandte Chemie (International Ed. in English)
|May 20, 2025
PubMed
Summary

Researchers developed a bispecific proteomimetic, CHDBI4, that binds both MDM2 and Ras. This novel molecular glue reduces cellular Ras levels, offering a new therapeutic strategy for targeting multiple protein interactions.

Keywords:
Constrained peptidesMolecular gluesProtein–protein interactionsProteomimeticsRas

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Area of Science:

  • Biochemistry
  • Molecular Biology
  • Drug Discovery

Background:

  • Bifunctional ligands that modulate protein-protein interactions are promising therapeutic agents.
  • Proteomimetics, such as crosslinked helix dimers (CHDs), can mimic protein structures to target specific interfaces.

Purpose of the Study:

  • To engineer a bispecific proteomimetic by incorporating a second binding epitope into a previously developed Ras-targeting molecule (CHDSOS).
  • To create a molecular glue capable of engaging both MDM2 and Ras simultaneously.

Main Methods:

  • Rational design of a bispecific proteomimetic (CHDBI4) by integrating a p53-derived epitope for MDM2 binding into CHDSOS.
  • Assessing the ability of CHDBI4 to bind both MDM2 and Ras.
  • Evaluating the effect of CHDBI4 on cellular Ras levels.

Main Results:

  • The engineered proteomimetic, CHDBI4, successfully associated with both MDM2 and Ras.
  • Treatment with CHDBI4 led to a reduction in cellular Ras levels.
  • Demonstrated proof of concept for a bispecific proteomimetic scaffold.

Conclusions:

  • Bispecific proteomimetics can be rationally designed to target multiple protein interfaces.
  • CHDBI4 represents a novel bispecific molecular glue with potential therapeutic applications.
  • This approach offers a versatile platform for developing targeted therapies against complex diseases.