A Selective Small-Molecule c-Myc Degrader Potently Regresses Lethal c-Myc Overexpressing Tumors

Area of Science:

• Oncology
• Molecular Biology
• Drug Discovery

Background:

• The MYC oncogene is implicated in numerous human cancers, often correlating with poor patient prognosis.
• Targeting the c-Myc protein has been a significant challenge in cancer therapy for over three decades.
• MYC overexpression is a critical factor in the development and progression of various malignancies.

Purpose of the Study:

• To introduce WBC100, a novel oral molecule glue designed for selective c-Myc protein degradation.
• To investigate the mechanism of action of WBC100 in cancer cells.
• To evaluate the efficacy and tolerability of WBC100 in preclinical cancer models.

Main Methods:

• WBC100 was developed as an oral active molecule glue targeting c-Myc.
• The drug's mechanism involves targeting the NLS1-Basic-NLS2 region of c-Myc.
• Degradation is mediated via the CHIP-ubiquitin E3 ligase and the 26S proteasome pathway, inducing apoptosis.
• Efficacy was assessed in xenograft mouse models of acute myeloid leukemia, pancreatic, and gastric cancers.

Main Results:

• WBC100 selectively degrades c-Myc protein, sparing other cellular proteins.
• The compound potently induces apoptosis in cancer cells overexpressing c-Myc.
• In vivo studies demonstrated potent regression of multiple lethal c-Myc-driven tumors.
• WBC100 exhibited good tolerability in preclinical models.

Conclusions:

• The NLS1-Basic-NLS2 region of c-Myc represents a druggable target, overcoming the 'undruggable' challenge.
• Single-agent WBC100 demonstrates potent anti-tumor activity through selective c-Myc proteolysis.
• This discovery opens new therapeutic avenues for pharmacologically targeting c-Myc in human cancers.