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Development of folate receptor targeting chimeras for cancer selective degradation of extracellular proteins

Author

Listed:
  • Yaxian Zhou

    (University of Wisconsin-Madison)

  • Chunrong Li

    (University of Wisconsin-Madison)

  • Xuankun Chen

    (University of Wisconsin-Madison)

  • Yuan Zhao

    (University of Wisconsin-Madison)

  • Yaxian Liao

    (University of Wisconsin-Madison)

  • Penghsuan Huang

    (University of Wisconsin-Madison)

  • Wenxin Wu

    (University of Wisconsin-Madison)

  • Nicholas S. Nieto

    (University of Wisconsin-Madison)

  • Lingjun Li

    (University of Wisconsin-Madison
    University of Wisconsin-Madison)

  • Weiping Tang

    (University of Wisconsin-Madison
    University of Wisconsin-Madison)

Abstract

Targeted protein degradation has emerged as a novel therapeutic modality to treat human diseases by utilizing the cell’s own disposal systems to remove protein target. Significant clinical benefits have been observed for degrading many intracellular proteins. Recently, the degradation of extracellular proteins in the lysosome has been developed. However, there have been limited successes in selectively degrading protein targets in disease-relevant cells or tissues, which would greatly enhance the development of precision medicine. Additionally, most degraders are not readily available due to their complexity. We report a class of easily accessible Folate Receptor TArgeting Chimeras (FRTACs) to recruit the folate receptor, primarily expressed on malignant cells, to degrade extracellular soluble and membrane cancer-related proteins in vitro and in vivo. Our results indicate that FRTAC is a general platform for developing more precise and effective chemical probes and therapeutics for the study and treatment of cancers.

Suggested Citation

  • Yaxian Zhou & Chunrong Li & Xuankun Chen & Yuan Zhao & Yaxian Liao & Penghsuan Huang & Wenxin Wu & Nicholas S. Nieto & Lingjun Li & Weiping Tang, 2024. "Development of folate receptor targeting chimeras for cancer selective degradation of extracellular proteins," Nature Communications, Nature, vol. 15(1), pages 1-14, December.
    • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-52685-9
    DOI: 10.1038/s41467-024-52685-9
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    References listed on IDEAS

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    1. Jingming Zhang & Anastasia Rakhimbekova & Xiaojiang Duan & Qingqing Yin & Catherine A. Foss & Yan Fan & Yangyang Xu & Xuesong Li & Xuekang Cai & Zsofia Kutil & Pengyuan Wang & Zhi Yang & Ning Zhang & , 2021. "A prostate-specific membrane antigen activated molecular rotor for real-time fluorescence imaging," Nature Communications, Nature, vol. 12(1), pages 1-11, December.
    2. Steven M. Banik & Kayvon Pedram & Simon Wisnovsky & Green Ahn & Nicholas M. Riley & Carolyn R. Bertozzi, 2020. "Lysosome-targeting chimaeras for degradation of extracellular proteins," Nature, Nature, vol. 584(7820), pages 291-297, August.
    3. Chen Chen & Jiyuan Ke & X. Edward Zhou & Wei Yi & Joseph S. Brunzelle & Jun Li & Eu-Leong Yong & H. Eric Xu & Karsten Melcher, 2013. "Structural basis for molecular recognition of folic acid by folate receptors," Nature, Nature, vol. 500(7463), pages 486-489, August.
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