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

• Published in: Nature communications 2024-10, Vol.15 (1), p.8695-14, Article 8695
• Main Authors: Zhou, Yaxian, Li, Chunrong, Chen, Xuankun, Zhao, Yuan, Liao, Yaxian, Huang, Penghsuan, Wu, Wenxin, Nieto, Nicholas S., Li, Lingjun, Tang, Weiping
• Format: Article
• Language: English
• Subjects: 13; 13/1; 13/105; 13/106; 13/109; 13/31; 13/51; 13/89; 14; 14/1; 14/19; 14/35; 59; 631/154/51/1568; 631/45/474; 639/638/309/2144; 64; 64/60; 692/4028/67/1059/153; 82/1; Animals; Biocompatibility; Biodegradation; Cancer; Cell Line, Tumor; Chimeras; Degradation; Female; Folate Receptor 1 - genetics; Folate Receptor 1 - metabolism; Folate Receptors, GPI-Anchored - metabolism; Folic acid; Folic Acid - metabolism; Humanities and Social Sciences; Humans; In vivo methods and tests; Lysosomes - metabolism; Mice; Mice, Nude; multidisciplinary; Neoplasm Proteins - genetics; Neoplasm Proteins - metabolism; Neoplasms - drug therapy; Neoplasms - genetics; Neoplasms - metabolism; Precision medicine; Proteins; Proteolysis; Receptors; Science; Science (multidisciplinary); Toxicity; Vitamin B; Xenograft Model Antitumor Assays
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-024-52685-9

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. Selective protein degradation in disease-relevant cells or tissues has seen limited success. Hence, the authors develop Folate Receptor Targeting Chimeras (FRTACs) to specifically target proteins in cancer cells, aiming to reduce on-target, off-tumor toxicity.