Recent Advances in Pro-PROTAC Development to Address On-Target Off-Tumor Toxicity
Related Experiment Video
Updated: Jul 26, 2025
High-Throughput Cellular Profiling of Targeted Protein Degradation Compounds Using HiBiT CRISPR Cell Lines
Published on: November 9, 2020
Chuanjie Chen1,2, Yiwen Yang3, Zhe Wang3
1Drug Discovery & Development Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
Abstract:
Proteolysis-targeting chimera (PROTAC) technology represents a novel and promising modality for targeted protein degradation with transformative implications for the clinical management of various diseases. Despite notable advantages, the possibility of on-target off-tumor toxicity in healthy cells represents a critical challenge to clinical applications in cancer treatment. Researchers are currently exploring strategies to enhance targeted degradation activity in a cell-selective manner to minimize undesirable side effects. In this Perspective, we highlight innovative approaches for prodrug-based PROTACs (pro-PROTACs) that facilitate tumor-targeted release. The development of such approaches may further expand the range of potential applications of PROTAC technology within drug development.
Insights
Proteolysis-targeting chimeras (PROTACs) offer targeted protein degradation but face on-target, off-tumor toxicity. Prodrug-based PROTACs (pro-PROTACs) are emerging to enhance tumor-specific delivery and minimize side effects.
Area of Science:
- Biochemistry
- Molecular Biology
- Drug Discovery
Background:
- Proteolysis-targeting chimera (PROTAC) technology enables targeted protein degradation.
- PROTACs show promise for treating various diseases, including cancer.
- On-target, off-tumor toxicity in healthy cells is a significant challenge for PROTAC clinical applications.
Purpose of the Study:
- To highlight innovative strategies for enhancing cell-selective PROTAC activity.
- To discuss prodrug-based PROTACs (pro-PROTACs) for tumor-targeted release.
- To explore the potential of pro-PROTACs in expanding PROTAC technology applications.
Main Methods:
- Review of current research on PROTAC technology.
- Analysis of strategies for achieving cell-selective protein degradation.
- Exploration of prodrug approaches for targeted PROTAC delivery.
Main Results:
- Prodrug-based PROTACs (pro-PROTACs) offer a strategy for tumor-targeted release.
- These approaches aim to minimize on-target, off-tumor toxicity.
- Pro-PROTACs may broaden the therapeutic applications of PROTAC technology.
Conclusions:
- Innovative prodrug strategies are crucial for safe and effective PROTAC-based cancer therapy.
- Pro-PROTACs represent a promising advancement in targeted protein degradation.
- Further development of pro-PROTACs could significantly impact drug development and clinical outcomes.
Related Concept Videos
02:57Targeted Cancer Therapies
There are several types of targeted therapies against...
01:27Tumor Immunotherapy
01:26Targets for Drug Action: Overview
Receptors are either membrane-spanning or intracellular proteins, which upon binding a ligand, get activated and transmit the signal downstream to elicit a response. Drugs bind receptors, either mimicking the action of endogenous ligands or blocking the receptor activity to bring about a modified response. Nearly 35% of approved drugs target the G...
02:50Combination Therapies and Personalized Medicine
The combination of the drug acetazolamide and sulforaphane is a good example of combination therapy to treat cancer. The cells in the interior of a large tumor often die due to the hypoxic and...