Functional inhibition of c-Myc using novel inhibitors identified through "hot spot" targeting

Area of Science:

• Oncology
• Structural Biology
• Drug Discovery

Background:

• Protein-protein interactions are vital in biological processes and disease.
• The transcription factor c-Myc is crucial for cellular homeostasis but its deregulation is linked to cancer.
• The disordered nature of c-Myc presents challenges for developing targeted cancer therapeutics.

Purpose of the Study:

• To identify hot spot residues at the c-Myc/Myc-associated factor X interface for small molecule targeting.
• To screen for and validate inhibitors of c-Myc activity using computational and biophysical methods.
• To demonstrate the potential for targeting disordered proteins like c-Myc in cancer therapy.

Main Methods:

• In silico alanine scanning mutagenesis to identify hot spot residues in the c-Myc/Myc-associated factor X interface.
• Conformation ensemble approach for screening potential small molecule inhibitors.
• Fluorescence-based biophysical experiments and cell-based assays to validate inhibitor binding and efficacy.

Main Results:

• Identified specific hot spot residues within the disordered c-Myc/Myc-associated factor X interface.
• Screened and identified hit molecules that bind noncovalently to these hot spot residues.
• Demonstrated in vitro potency of hit compounds against c-Myc-expressing cancer and stem cells by deregulating c-Myc activity.
• Confirmed stable binding of hit compounds to the disordered c-Myc protein through biophysical and computational studies.

Conclusions:

• Effective drug targeting of the disordered c-Myc protein is achievable by identifying hot spot residues.
• The identified inhibitors show promise for developing novel cancer therapeutics against c-Myc-driven cancers.
• This study provides a framework for targeting other intrinsically disordered proteins in drug discovery.