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

Yaxian Zhou, Chunrong Li, Xuankun Chen, Yuan Zhao, Yaxian Liao, Penghsuan Huang, Wenxin Wu, Nicholas S. Nieto, Lingjun Li and Weiping Tang ()
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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
Weiping Tang: University of Wisconsin-Madison

Nature Communications, 2024, vol. 15, issue 1, 1-14

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41467-024-52685-9

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