Targeting oncogenic transcriptional factor c-myc by oligonucleotide PROTAC for the treatment of hepatocellular...

Area of Science:

• Oncology
• Molecular Biology
• Drug Discovery

Background:

• Hepatocellular carcinoma (HCC) presents limited therapeutic options and high mortality.
• The transcription factor c-Myc is a key oncogene in HCC, making it a critical therapeutic target.
• Targeting c-Myc effectively in HCC has been historically challenging.

Purpose of the Study:

• To develop novel oligonucleotide-based proteolysis targeting chimeras (PROTACs) for targeted c-Myc degradation in HCC.
• To investigate the mechanism of action and therapeutic efficacy of these novel PROTACs in HCC models.

Main Methods:

• Conjugation of VH032 with a DNA sequence targeting the c-Myc complex to create oligonucleotide PROTACs (MP-16 and MP-17).
• Assessment of c-Myc degradation via the ubiquitin-proteasome system.
• Evaluation of HCC cell proliferation suppression.
• In vivo efficacy and safety studies in a mouse model of HCC.

Main Results:

• MP-16 and MP-17 successfully induced targeted degradation of c-Myc by forming a VHL/PROTAC/c-Myc ternary complex.
• These PROTACs suppressed HCC cell proliferation.
• MP-16 and MP-17 demonstrated significant inhibition of HCC tumor growth in vivo with good drug safety.

Conclusions:

• Oligonucleotide PROTACs (MP-16, MP-17) represent a novel strategy for degrading c-Myc in HCC.
• This approach provides a new lead structure for developing effective HCC therapies targeting c-Myc.