Protein Degraders: A Promising Approach to Cancer Therapy

Introduction:
In a groundbreaking scientific paper titled “Protein degraders enter the clinic — a new approach to cancer therapy,” researchers Deborah Chirnomas, Keith R. Hornberger, and Craig M. Crews discuss the development and potential of protein degraders as a novel therapeutic modality for treating cancer. This emerging field aims to harness the cell’s natural protein-degradation machinery, known as the ubiquitin-proteasome system, to selectively target disease-causing proteins for elimination.

Challenges with Current Cancer Therapies:
Traditional cancer treatments such as chemotherapy, radiotherapy, and surgery have limitations, including toxicities, morbidities, and adverse effects on noncancerous cells. The advent of small-molecule inhibitors brought about a new era of precision medicine, but they are limited in their ability to target proteins without suitable binding pockets and require continuous high concentrations for therapeutic effects.

The Promise of Protein Degraders:
Protein degraders, specifically heterobifunctional protein degraders like PROTACs (PROteolysis TArgeting Chimeras), offer several advantages over small-molecule inhibitors. They can selectively eliminate target proteins, even those previously considered “undruggable.” Unlike occupancy-driven pharmacology, protein degraders have event-driven pharmacology, allowing for sub-stoichiometric drug concentrations for activity. Moreover, protein degraders can act iteratively and target multiple copies of a protein of interest.

Progress in Clinical Trials:
Since 2019, protein degraders have entered clinical testing, with 18 of them currently in phase I or phase I/II clinical trials involving patients with various tumor types. The initial safety, efficacy, and pharmacokinetic data from these studies are starting to emerge, showing promising activity as cancer therapies. Preliminary data on protein degraders targeting androgen receptor, estrogen receptor, and BTK have demonstrated encouraging clinical activity in prostate cancer, breast cancer, and chronic lymphocytic leukemia, respectively.

Future Directions:
The paper highlights the progress made in protein degrader development, the preclinical research supporting their clinical entry, and the ongoing studies evaluating their efficacy. Although more evidence is needed, protein degraders represent a new class of drugs with significant potential for the treatment of various diseases, including cancer. Further clinical studies will shed more light on their effectiveness and potential challenges.

Conclusion:
Protein degraders have emerged as a promising therapeutic approach for cancer treatment. This innovative strategy capitalizes on the cell’s natural protein-degradation machinery to selectively eliminate disease-causing proteins. After years of research and preclinical testing, protein degraders have entered clinical trials, demonstrating encouraging preliminary results. While more data is eagerly awaited, protein degraders offer hope as potential therapies for a range of diseases. The field continues to evolve, and the future looks promising for this novel class of drugs.

Citation:
Chirnomas, D., Hornberger, K.R. & Crews, C.M. Protein degraders enter the clinic — a new approach to cancer therapy. Nat Rev Clin Oncol 20, 265–278 (2023). https://doi.org/10.1038/s41571-023-00736-3