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

• Published in: Journal of the American Chemical Society Vol. 145; no. 16; pp. 9334 - 9342
• Main Authors: Li, Xintong, Zhang, Ze, Gao, Fangyan, Ma, Yuxuan, Wei, Dongying, Lu, Zhangwei, Chen, Siqi, Wang, Mengqi, Wang, Yueyao, Xu, Kun, Wang, Runtian, Xu, Feng, Chen, Jia-Yu, Zhu, Chengjun, Li, Zhe, Yu, Hanyang, Guan, Xiaoxiang
• Format: Journal Article
• Language: English
• Published: United States American Chemical Society 26.04.2023
• Subjects: Animals; Antineoplastic Agents - pharmacology; Antineoplastic Agents - therapeutic use; breast neoplasms; Cell Line, Tumor; Cell Proliferation; cyclin-dependent kinase; Disease Models, Animal; DNA; Genes, myc; Humans; Mice; nucleotide sequences; oligonucleotides; prognosis; proteolysis; therapeutics; Transcription Factors; Triple Negative Breast Neoplasms - pathology
• ISSN: 0002-7863; 1520-5126; 1520-5126
• DOI: 10.1021/jacs.3c02619

Triple-negative breast cancer (TNBC) is highly aggressive with a poor clinical prognosis and no targeted therapy. The c-Myc protein is a master transcription factor and a potential therapeutic target for TNBC. In this study, we develop a PROTAC (PROteolysis TArgeting Chimera) based on TNA (threose nucleic acid) and DNA that effectively targets and degrades c-Myc. The TNA aptamer is selected in vitro to bind the c-Myc/Max heterodimer and appended to the E-box DNA sequence to create a high-affinity, biologically stable bivalent binder. The TNA-E box-pomalidomide (TEP) conjugate specifically degrades endogenous c-Myc/Max, inhibits TNBC cell proliferation, and sensitizes TNBC cells to the cyclin-dependent kinase inhibitor palbociclib in vitro. In a mouse TNBC model, combination therapy with TEP and palbociclib potently suppresses tumor growth. This study offers a promising nucleic acid-based PROTAC modality for both chemical biology studies and therapeutic interventions of TNBC.