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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| Veröffentlicht in: | Journal of the American Chemical Society Jg. 145; H. 16; S. 9334 |
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26.04.2023
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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. |
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| 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 |
| Author_xml | – sequence: 1 givenname: Xintong surname: Li fullname: Li, Xintong organization: Department of Oncology, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, China – sequence: 2 givenname: Ze orcidid: 0000-0002-8570-8790 surname: Zhang fullname: Zhang, Ze organization: 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), Nanjing University, Nanjing 210023, China – sequence: 3 givenname: Fangyan surname: Gao fullname: Gao, Fangyan organization: Department of Oncology, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, China – sequence: 4 givenname: Yuxuan surname: Ma fullname: Ma, Yuxuan organization: State Key Laboratory of Analytical Chemistry for Life Science, Department of Biomedical Engineering, College of Engineering and Applied Sciences, Nanjing University, Nanjing 210023, China – sequence: 5 givenname: Dongying surname: Wei fullname: Wei, Dongying organization: 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), Nanjing University, Nanjing 210023, China – sequence: 6 givenname: Zhangwei surname: Lu fullname: Lu, Zhangwei organization: State Key Laboratory of Analytical Chemistry for Life Science, Department of Biomedical Engineering, College of Engineering and Applied Sciences, Nanjing University, Nanjing 210023, China – sequence: 7 givenname: Siqi surname: Chen fullname: Chen, Siqi organization: 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), Nanjing University, Nanjing 210023, China – sequence: 8 givenname: Mengqi surname: Wang fullname: Wang, Mengqi organization: State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Chemistry and Biomedicine Innovation Center (ChemBIC), Nanjing University, Nanjing 210023, China – sequence: 9 givenname: Yueyao surname: Wang fullname: Wang, Yueyao organization: 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), Nanjing University, Nanjing 210023, China – sequence: 10 givenname: Kun surname: Xu fullname: Xu, Kun organization: Department of Oncology, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, China – sequence: 11 givenname: Runtian orcidid: 0000-0001-7434-3944 surname: Wang fullname: Wang, Runtian organization: Department of Oncology, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, China – sequence: 12 givenname: Feng surname: Xu fullname: Xu, Feng organization: Department of Oncology, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, China – sequence: 13 givenname: Jia-Yu surname: Chen fullname: Chen, Jia-Yu organization: State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Chemistry and Biomedicine Innovation Center (ChemBIC), Nanjing University, Nanjing 210023, China – sequence: 14 givenname: Chengjun surname: Zhu fullname: Zhu, Chengjun organization: Department of Oncology, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, China – sequence: 15 givenname: Zhe orcidid: 0000-0002-2755-2409 surname: Li fullname: Li, Zhe organization: State Key Laboratory of Analytical Chemistry for Life Science, Department of Biomedical Engineering, College of Engineering and Applied Sciences, Nanjing University, Nanjing 210023, China – sequence: 16 givenname: Hanyang orcidid: 0000-0003-1257-1735 surname: Yu fullname: Yu, Hanyang organization: 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), Nanjing University, Nanjing 210023, China – sequence: 17 givenname: Xiaoxiang surname: Guan fullname: Guan, Xiaoxiang organization: Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Personalized Cancer Medicine, Nanjing Medical University, Nanjing 210029, China |
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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 Cell Line, Tumor Cell Proliferation Disease Models, Animal Genes, myc Humans Mice 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 |
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