c-Myc-Targeting PROTAC Based on a TNA-DNA Bivalent Binder for Combination Therapy of Triple-Negative Breast Cancer

Area of Science:

• Biochemistry
• Molecular Biology
• Cancer Therapeutics

Background:

• Triple-negative breast cancer (TNBC) is an aggressive subtype lacking targeted therapies.
• The c-Myc oncoprotein is a critical driver of TNBC and a potential therapeutic target.
• Current treatment strategies for TNBC are limited, necessitating novel therapeutic approaches.

Purpose of the Study:

• To develop a novel nucleic acid-based Proteolysis Targeting Chimera (PROTAC) to degrade the c-Myc oncoprotein.
• To evaluate the efficacy of the developed PROTAC in inhibiting TNBC cell proliferation and sensitizing cells to existing therapies.
• To assess the therapeutic potential of the PROTAC in preclinical TNBC models.

Main Methods:

• Selection of a TNA (threose nucleic acid) aptamer targeting the c-Myc/Max heterodimer.
• Conjugation of the TNA aptamer with an E-box DNA sequence and pomalidomide to create a bivalent PROTAC (TEP).
• In vitro assessment of TEP-mediated c-Myc/Max degradation, TNBC cell proliferation inhibition, and drug sensitization.
• In vivo evaluation of TEP and palbociclib combination therapy in a mouse TNBC model.

Main Results:

• The TNA-E box-pomalidomide (TEP) conjugate effectively targets and degrades endogenous c-Myc/Max.
• TEP significantly inhibits TNBC cell proliferation in vitro.
• TEP sensitizes TNBC cells to the cyclin-dependent kinase inhibitor palbociclib.
• Combination therapy of TEP and palbociclib potently suppresses tumor growth in a mouse TNBC model.

Conclusions:

• Nucleic acid-based PROTACs represent a viable modality for targeting aggressive cancers like TNBC.
• The developed TEP conjugate demonstrates significant therapeutic potential for TNBC.
• This approach offers a promising strategy for both chemical biology research and future clinical interventions in TNBC.