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 inJournal 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
LanguageEnglish
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
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Abstract 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.
AbstractList 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.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.
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.
Author Wang, Mengqi
Li, Xintong
Li, Zhe
Ma, Yuxuan
Wei, Dongying
Lu, Zhangwei
Wang, Yueyao
Wang, Runtian
Yu, Hanyang
Gao, Fangyan
Zhang, Ze
Xu, Feng
Xu, Kun
Chen, Jia-Yu
Zhu, Chengjun
Guan, Xiaoxiang
Chen, Siqi
AuthorAffiliation Nanjing Medical University
Department of Oncology
Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Personalized Cancer Medicine
State Key Laboratory of Coordination Chemistry, Department of Biomedical Engineering, College of Engineering and Applied Sciences, Jiangsu Key Laboratory of Artificial Functional Materials, Chemistry and Biomedicine Innovation Center (ChemBIC)
State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Chemistry and Biomedicine Innovation Center (ChemBIC)
State Key Laboratory of Analytical Chemistry for Life Science, Department of Biomedical Engineering, College of Engineering and Applied Sciences
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– name: Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Personalized Cancer Medicine
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  orcidid: 0000-0003-1257-1735
  surname: Yu
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  email: hanyangyu@nju.edu.cn
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  givenname: Xiaoxiang
  surname: Guan
  fullname: Guan, Xiaoxiang
  email: xguan@njmu.edu.cn
  organization: Nanjing Medical University
BackLink https://www.ncbi.nlm.nih.gov/pubmed/37068218$$D View this record in MEDLINE/PubMed
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Snippet 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...
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SubjectTerms 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
Title c‑Myc-Targeting PROTAC Based on a TNA-DNA Bivalent Binder for Combination Therapy of Triple-Negative Breast Cancer
URI http://dx.doi.org/10.1021/jacs.3c02619
https://www.ncbi.nlm.nih.gov/pubmed/37068218
https://www.proquest.com/docview/2802884486
https://www.proquest.com/docview/3040429443
Volume 145
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