Going on the offense: PROTACs as cancer therapy

Reading time: 3 minutes

Kedar Puvar

Diseases are typically caused by defective or malicious proteins. Traditionally, treatments for these diseases use a strategy of inhibition – use a small molecule that can block the offending protein from carrying out its function and thereby, bring things back to normal. But what if we went one step further? What if instead of merely blocking disease-causing proteins, we made them disappear entirely?

In 2001, work done by a team of researchers led by Craig Crews and Ray Deshaies brought this concept into the realm of possibility. They created a molecule  dubbed protein-targeting chimera, or PROTAC. This innovative molecule brings the might of the cell’s natural protein-shredding machinery to bear, removing troublesome proteins with relative ease. The approach has led to an explosion of research and billions of dollars has been invested into getting this treatment to the clinic.

In one of last months Oncobites articles, “The Ubiquitin System and Why Researchers Are Targeting it for Cancer Therapy”, we looked at how cells get rid of proteins that are deemed unwanted. One of the proteins involved in this process is the proteasome, a molecular machine that takes apart a targeted protein into its components. For a protein to be sent to the proteasome, it must be tagged with ubiquitin. PROTACs are bi-functional molecules, where one end binds to the target protein, and the other end binds to an E3 ubiquitin ligase. Once together, the ligase will begin ubiquitinating the target, which then causes the target to be sent to the  proteasome and degraded. All that’s required for ubiquitination is proximity, which is what the PROTAC provides. The ability to mark any protein for degradation gives these PROTACs huge versatility. Furthermore, we can potentially take out proteins thought to be “undruggable” by using PROTACs – all you need is something that can bind to your target protein.

There are many ways this can be applied to cancer. Name any cancer-causing protein and you can probably design a PROTAC against it. Indeed, the first ever example, PROTAC-1, targeted and degraded MetAP2, a protein thought to be involved in solid tumor development. This past year a PROTAC against BRD4, a protein that stimulates the activation of cancer-causing oncogenes, was found to have potent anticancer activity. Over the past several years a whole host of such PROTACs has been built up, with more being developed on a regular basis.

Of course, some challenges lie ahead. The relatively bulky nature of the first generation of PROTACs caused  them to be inefficient at entering human cells, requiring a dose too large to be practical. Another limitation is the availability of chemical groups that can bind onto proteins of interest, something that will require additional research efforts to develop. However,much progress has been made in streamlining these molecules to make them more viable as medicines, and in-vivo experiments in mice and human cell lines are becoming increasingly common.

Arvinas, a company founded by Craig Crews, has generated quite the buzz, announcing collaborations with giants such as Pfizer, Merck, and Genentech to work on PROTAC technology. Encouragingly, the company has just begun the first dosing of cancer patients in clinical trials involving a PROTAC. The target in this case? An androgen receptor known to play a critical role in prostate cancer. They are also designing a PROTAC for the estrogen receptor as a treatment for breast cancer patients, scheduled to enter Phase 1 trials sometime this summer. Many more are also in the works. Keep your eyes on this technology – as futuristic as it seems, it may hit the market sooner than you think.

Works Discussed:

Deshaies, R. J. (2015). Protein degradation: Prime time for PROTACs. Nature Chemical Biology, 11(9), 634–635. https://doi.org/10.1038/nchembio.1887

Gu, S., Cui, D., Chen, X., Xiong, X., & Zhao, Y. (2018). PROTACs: An Emerging Targeting Technique for Protein Degradation in Drug Discovery. BioEssays, 40(4), 1700247. https://doi.org/10.1002/bies.201700247

Sakamoto, K. M., Kim, K. B., Kumagai, A., Mercurio, F., Crews, C. M., & Deshaies, R. J. (2001). Protacs: Chimeric molecules that target proteins to the Skp1–Cullin–F box complex for ubiquitination and degradation. Proceedings of the National Academy of Sciences, 98(15), 8554–8559. https://doi.org/10.1073/pnas.141230798

Zhang, X., Lee, H. C., Shirazi, F., Baladandayuthapani, V., Lin, H., Kuiatse, I., … Orlowski, R. Z. (2018). Protein targeting chimeric molecules specific for bromodomain and extra-terminal motif family proteins are active against pre-clinical models of multiple myeloma. Leukemia, 32(10), 2224. https://doi.org/10.1038/s41375-018-0044-x