Advancing targeted protein degradation for cancer therapy
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Updated: Nov 2, 2025
High-Throughput Cellular Profiling of Targeted Protein Degradation Compounds Using HiBiT CRISPR Cell Lines
Published on: November 9, 2020
Brandon Dale1,2,3,4, Meng Cheng5,6, Kwang-Su Park1,2,3,4
1Mount Sinai Center for Therapeutics Discovery, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
Abstract:
The human proteome contains approximately 20,000 proteins, and it is estimated that more than 600 of them are functionally important for various types of cancers, including nearly 400 non-enzyme proteins that are challenging to target by traditional occupancy-driven pharmacology. Recent advances in the development of small-molecule degraders, including molecular glues and heterobifunctional degraders such as proteolysis-targeting chimeras (PROTACs), have made it possible to target many proteins that were previously considered undruggable. In particular, PROTACs form a ternary complex with a hijacked E3 ubiquitin ligase and a target protein, leading to polyubiquitination and degradation of the target protein. The broad applicability of this approach is facilitated by the flexibility of individual E3 ligases to recognize different substrates. The vast majority of the approximately 600 human E3 ligases have not been explored, thus presenting enormous opportunities to develop degraders that target oncoproteins with tissue, tumour and subcellular selectivity. In this Review, we first discuss the molecular basis of targeted protein degradation. We then offer a comprehensive account of the most promising degraders in development as cancer therapies to date. Lastly, we provide an overview of opportunities and challenges in this exciting field.
Insights
New small-molecule degraders, like proteolysis-targeting chimeras (PROTACs), offer a way to target previously undruggable cancer proteins. This approach hijacks E3 ligases to degrade disease-causing proteins, opening new therapeutic avenues.
Area of Science:
- Biochemistry
- Molecular Biology
- Oncology
Background:
- The human proteome has ~20,000 proteins, with over 600 implicated in cancer.
- Nearly 400 cancer-related proteins are non-enzymatic and difficult to target with traditional drugs.
- Small-molecule degraders, including proteolysis-targeting chimeras (PROTACs), enable targeting of previously undruggable proteins.
Purpose of the Study:
- To review the molecular mechanisms of targeted protein degradation.
- To provide a comprehensive overview of promising PROTACs in cancer therapy development.
- To discuss the opportunities and challenges in the field of targeted protein degradation for cancer treatment.
Main Methods:
- Discussion of the molecular basis of targeted protein degradation.
- Review of current PROTAC technology and its application in cancer therapy.
- Analysis of the potential of E3 ligase targeting for selective oncoprotein degradation.
Main Results:
- PROTACs induce target protein degradation by forming a ternary complex with an E3 ubiquitin ligase.
- The flexibility of E3 ligases allows for broad substrate recognition and targeted degradation.
- Exploration of the vast majority of human E3 ligases presents opportunities for selective cancer therapies.
Conclusions:
- Targeted protein degradation using PROTACs is a promising strategy for treating cancer.
- The development of novel degraders offers potential for tissue, tumor, and subcellular selectivity.
- Further research into E3 ligases and degrader development holds significant promise for oncology.
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