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

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 n...

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Published in:Journal of the American Chemical Society Vol. 145; no. 16; p. 9334
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 26.04.2023
Subjects:
Animals
Antineoplastic Agents - pharmacology
Antineoplastic Agents - therapeutic use
Cell Line, Tumor
Cell Proliferation
Disease Models, Animal
Genes, myc
Humans
Mice
Transcription Factors
Triple Negative Breast Neoplasms - pathology
ISSN:1520-5126, 1520-5126
Online Access:Get more information
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Summary: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.
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ISSN:1520-5126
1520-5126
DOI:10.1021/jacs.3c02619