Development of DuoMYC: a synthetic cell penetrant miniprotein that efficiently inhibits the oncogenic transcription...

Area of Science:

• Oncology
• Molecular Biology
• Drug Discovery

Background:

• The MYC transcription factor is a master regulator implicated in numerous human cancers.
• MYC is considered 'undruggable' due to its lack of classical binding pockets and presence of intrinsically disordered regions.
• Targeting MYC is a significant challenge in cancer drug development.

Purpose of the Study:

• To engineer novel synthetic miniproteins capable of inhibiting MYC-driven transcription.
• To develop an alternative therapeutic strategy for targeting MYC, overcoming its 'undruggable' status.
• To assess the efficacy of engineered miniproteins in inhibiting MYC activity in cancer cells.

Main Methods:

• Structure-based design of synthetic miniproteins.
• Solid phase peptide synthesis and site-specific crosslinking to create miniproteins.
• Assessing DNA binding affinity (K_D) and cellular potency (IC₅₀) using reporter gene assays and RNA sequencing.

Main Results:

• Engineered miniproteins successfully bind to the MYC target DNA sequence (E-Box) with high affinity.
• The lead variant, DuoMYC, demonstrated submicromolar potency in inhibiting MYC-driven transcription within cells.
• DuoMYC exhibited superior efficacy compared to other recently developed MYC inhibitors.

Conclusions:

• Engineered synthetic miniproteins represent a promising therapeutic approach for targeting challenging intracellular proteins like MYC.
• This strategy offers a viable alternative to direct MYC inhibition for cancer treatment.
• The development of DuoMYC highlights the potential of synthetic protein therapeutics in oncology.