Cancer Selective Target Degradation by Folate-Caged PROTACs

Overview

Journal J Am Chem Soc

Publisher American Chemical Society

Specialty Chemistry

Date 2021 May 10

PMID 33970635

Citations 68

Authors

Jing Liu

He Chen

Yi Liu

Yudao Shen

Fanye Meng

H Umit Kaniskan

Jian Jin

Wenyi Wei

Affiliations

Soon will be listed here.

Abstract

PROTACs (proteolysis targeting chimeras) are an emerging class of promising therapeutic modalities that degrade intracellular protein targets by hijacking the cellular ubiquitin-proteasome system. However, potential toxicity of PROTACs in normal cells due to the off-tissue on-target degradation effect limits their clinical applications. Precise control of a PROTAC's on-target degradation activity in a tissue-selective manner could minimize potential toxicity/side-effects. To this end, we developed a cancer cell selective delivery strategy for PROTACs by conjugating a folate group to a ligand of the VHL E3 ubiquitin ligase, to achieve targeted degradation of proteins of interest (POIs) in cancer cells versus noncancerous normal cells. We show that our folate-PROTACs, including BRD PROTAC (folate-ARV-771), MEK PROTAC (folate-MS432), and ALK PROTAC (folate-MS99), are capable of degrading BRDs, MEKs, and ALK, respectively, in a folate receptor-dependent manner in cancer cells. This design provides a generalizable platform for PROTACs to achieve selective degradation of POIs in cancer cells.

Citing Articles

Navigating PROTACs in Cancer Therapy: Advancements, Challenges, and Future Horizons.

Ibrahim S, Khan M, Khurram I, Rehman R, Rauf A, Ahmad Z Food Sci Nutr. 2025; 13(2):e70011.

PMID: 39898116 PMC: 11786021. DOI: 10.1002/fsn3.70011.

A patent review of von Hippel-Lindau (VHL)-recruiting chemical matter: E3 ligase ligands for PROTACs and targeted protein degradation (2019-present).

Urbina A, Hallatt A, Robertson J, Ciulli A Expert Opin Ther Pat. 2025; :1-42.

PMID: 39834300 PMC: 11875441. DOI: 10.1080/13543776.2024.2446232.

Dual-Performing Vinyltetrazine for Rapid, Selective Bioconjugation and Functionalization of Cysteine Proteins.

Chang M, Xu H, Dong Y, Gnawali G, Bi F, Wang W ACS Chem Biol. 2024; 20(1):153-161.

PMID: 39707969 PMC: 11747768. DOI: 10.1021/acschembio.4c00610.

Precision-engineered PROTACs minimize off-tissue effects in cancer therapy.

Shi J, Wang L, Zeng X, Xie C, Meng Z, Campbell A Front Mol Biosci. 2024; 11:1505255.

PMID: 39649701 PMC: 11621628. DOI: 10.3389/fmolb.2024.1505255.

Protacs in cancer therapy: mechanisms, design, clinical trials, and future directions.

Vikal A, Maurya R, Patel B, Sharma R, Patel P, Patil U Drug Deliv Transl Res. 2024; .

PMID: 39614036 DOI: 10.1007/s13346-024-01754-z.

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