2. Academic Validation
  3. Discovery of a proteolysis targeting chimera (PROTAC) as a potent regulator of FOXP3

Discovery of a proteolysis targeting chimera (PROTAC) as a potent regulator of FOXP3

  • Bioorg Med Chem Lett. 2024 Nov 1:112:129945. doi: 10.1016/j.bmcl.2024.129945.
Bowen Yang 1,  Yanhong Cen 2,  Fangfang Li 3,  Yikui Li 4,  Bichun Chen 5,  Jiwei Zheng 6,  Zhongliang Tang 7,  Qiang Gao 8,  Lijing Fang 9,  Fan Pan 10
Affiliations

Affiliations

  • 1 Tianjin University of Science and Technology, Tianjin 300457, China; Guangdong Key Laboratory of Nanomedicine, CAS-HK Joint Lab of Biomaterials, CAS Key Laboratory of Biomedical Imaging Science and System, Institute of Biomedicine and Biotechnology, Shenzhen Institute of Advanced Technology (SIAT), Chinese Academy of Sciences (CAS), Shenzhen 518055, China. Electronic address: bw.yang@siat.ac.cn.
  • 2 Guangdong Key Laboratory of Nanomedicine, CAS-HK Joint Lab of Biomaterials, CAS Key Laboratory of Biomedical Imaging Science and System, Institute of Biomedicine and Biotechnology, Shenzhen Institute of Advanced Technology (SIAT), Chinese Academy of Sciences (CAS), Shenzhen 518055, China; Department of Radiation Oncology, Ningbo No.2 Hospital, Ningbo, Zhejiang 315010, China. Electronic address: yh.c@siat.ac.cn.
  • 3 Guangdong Key Laboratory of Nanomedicine, CAS-HK Joint Lab of Biomaterials, CAS Key Laboratory of Biomedical Imaging Science and System, Institute of Biomedicine and Biotechnology, Shenzhen Institute of Advanced Technology (SIAT), Chinese Academy of Sciences (CAS), Shenzhen 518055, China; Department of Radiation Oncology, Henan Provincial Key Laboratory of Radiation Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, China. Electronic address: ff.li@siat.actin.cn.
  • 4 Guangdong Key Laboratory of Nanomedicine, CAS-HK Joint Lab of Biomaterials, CAS Key Laboratory of Biomedical Imaging Science and System, Institute of Biomedicine and Biotechnology, Shenzhen Institute of Advanced Technology (SIAT), Chinese Academy of Sciences (CAS), Shenzhen 518055, China. Electronic address: yk.li3@siat.ac.cn.
  • 5 Guangdong Key Laboratory of Nanomedicine, CAS-HK Joint Lab of Biomaterials, CAS Key Laboratory of Biomedical Imaging Science and System, Institute of Biomedicine and Biotechnology, Shenzhen Institute of Advanced Technology (SIAT), Chinese Academy of Sciences (CAS), Shenzhen 518055, China. Electronic address: bc.chen@siat.ac.cn.
  • 6 Guangdong Key Laboratory of Nanomedicine, CAS-HK Joint Lab of Biomaterials, CAS Key Laboratory of Biomedical Imaging Science and System, Institute of Biomedicine and Biotechnology, Shenzhen Institute of Advanced Technology (SIAT), Chinese Academy of Sciences (CAS), Shenzhen 518055, China. Electronic address: jw.zheng@siat.ac.cn.
  • 7 Tianjin University of Science and Technology, Tianjin 300457, China. Electronic address: zl.tang@siat.ac.cn.
  • 8 Tianjin University of Science and Technology, Tianjin 300457, China. Electronic address: gaoqiang@tust.edu.cn.
  • 9 Guangdong Key Laboratory of Nanomedicine, CAS-HK Joint Lab of Biomaterials, CAS Key Laboratory of Biomedical Imaging Science and System, Institute of Biomedicine and Biotechnology, Shenzhen Institute of Advanced Technology (SIAT), Chinese Academy of Sciences (CAS), Shenzhen 518055, China. Electronic address: lj.fang@siat.ac.cn.
  • 10 Guangdong Key Laboratory of Nanomedicine, CAS-HK Joint Lab of Biomaterials, CAS Key Laboratory of Biomedical Imaging Science and System, Institute of Biomedicine and Biotechnology, Shenzhen Institute of Advanced Technology (SIAT), Chinese Academy of Sciences (CAS), Shenzhen 518055, China. Electronic address: fan.pan@siat.ac.cn.
PMID: 39222889 DOI: 10.1016/j.bmcl.2024.129945
Abstract

Regulatory T (Treg) cells play a central role in immune homeostasis. Forkhead box P3 (Foxp3), a hallmark molecule in Treg cells, is a vital transcription factor for their development and function. Studies have shown that degradation of the Foxp3 could provide therapeutic benefits in achieving effective anti-tumor immunity. In this study, we designed three PROTAC molecules, P60-L1-VHL, P60-L2-VHL, and P60-L3-VHL, based on a 15-mer peptide inhibitor of Foxp3 (P60), and explored their potential in regulating Foxp3 expression and function. Our data show that, among these molecules, P60-L3-VHL can inhibit the expression and nuclear localization of Foxp3 in HEK 293 T and HeLa cells, respectively. Meanwhile, use of Proteasome Inhibitor in P60-L3-VHL treated cells revealed an increased Foxp3 expression, indicating that P60-L3-VHL mediates the inhibition of Foxp3 through its degradation in the Proteasome pathway. We further substantiate that P60-L3-VHL reduces the differentiation and Foxp3 expression in the in-vitro activated Treg cells. Overall, our findings suggest that P60-L3-VHL inhibits the differentiation of Treg cells by degrading the Foxp3, which may have potential implications in Cancer Immunotherapy.

Keywords

Foxp3; PROTAC; Tregs.

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