If you’re working in cancer drug discovery, it’s no secret that proteolysis targeting chimeras (PROTACs) hold great promise for developing innovative new treatments. We’ve seen that these bifunctional molecules can remove unwanted proteins by inducing selective intracellular proteolysis, making them potentially applicable in several areas of oncology. But despite all this burgeoning potential, the investigation of PROTACs as a viable drug option has only really just begun.
To help us explore some of the questions around the future of PROTACs, Matthew Cheeseman, Staff Scientist at The Institute of Cancer Research, will be attending our upcoming Drug Discovery 2018 conference (October 9th and 10th at the Excel Arena in London). Make sure you see his presentation on “using PROTACs as probes to study intracellular target engagement against proteins with unknown function” which will explore the topic of PROTAC drug discovery in-depth. Book your free place here!
Ahead of the event, we asked Matthew to describe some of the opportunities and challenges associated with PROTAC research, as well as to highlight why it’s such a rewarding and exciting area to get into. Here’s what he had to say…

How are PROTACs gaining traction as a cancer drug discovery technique?
Although we’ve been aware of the cellular protein degradation advantages of PROTACs for years, it is only recently that they have gained widespread traction as a viable way to control protein levels. PROTACs consist of two linked protein binding molecules, one of which can engage an E3 ubiquitin ligase, and the other a target protein meant for degradation. The difficulty was that initially there were very few molecules known with the ability to target E3 ligase. As Matthew explains, “while the idea of PROTACs has been known for some time, the challenge was finding the appropriate small molecules for their function”.
Several recent breakthroughs in the discovery of low-molecular weight, specific, and high affinity E3 ligands have enabled a new generation of highly potent PROTACs. These dramatically improved PROTACs have spurred on their applications in oncology therapeutic research. Matthew states that “now, we’re trying to develop a toolbox of different E3 ligase targeting small molecules and to understand the intricacies of the process”.

The advantages of PROTACs and the new age of drug discovery
PROTACs can be used to understand the effects of removing a protein from a cancer cell. In the past, we were only able to do this with genetic techniques such as RNAi and now more recently CRISPR. But Matthew says that “the problem with these techniques is that they involve clonal selection and hence they allow cells to adapt to that change”. With PROTACs, the moment you treat the cell, it starts to deplete the protein meaning that you get a more direct idea of the phenotype and what effect that has on the cancer cell. This gives us a really powerful tool in chemical biology to understand what the inherent functions of these proteins are.
The other side of PROTACs is their potential development as drugs. This is currently still in the early stages, but PROTAC drugs could provide a new way to target proteins. Matthew explains that “in the past, you would inhibit a protein with a small molecule – and while this small molecule would slow down the protein’s catalytic function, it wouldn’t stop it acting like a protein in other ways”. Proteins that are inhibited with small molecules can still act as scaffolds, bind to other proteins, and travel freely in the cell. With a PROTAC, the protein entirely disappears, so not only can it no longer perform as a catalyst, it can’t perform any of its other functions. You could potentially end up with a completely different phenotype than you would’ve previously seen with small molecule targeting drugs.
The importance of this is stressed by Matthew who says that “particularly in oncology, all of our validation tends to be through genetic techniques of depleting proteins. Using PROTACs as an alternative could help us develop many vital new therapeutics”.

The modern challenges of PROTACs research
One of the biggest challenges associated with recent PROTAC development is that because they need to bind simultaneously to the target protein and the E3 ligase, the molecules are larger and more complex than typical protein inhibitors. Their size could limit their pharmacokinetic (PK) capabilities. Matthew describes that “by the time you make this three-part molecule of protein, linker, and E3 ligase, it’s overly bulky, which makes it difficult to get it into cells”.
The size and complexity of PROTACs also affects their oral bioavailability. In the future, it is unlikely that they will be offered in tablet form, and more probable that they will have to be dosed intravenously (IV). This could limit their application to therapeutic areas whereby IV dosing is acceptable, such as oncology.

How are PROTACs driving future developments in drug discovery?

In terms of chemical tools, PROTACs might be used in the in vivo validation of targets. Matthew explains that “regularly, we go a long way through the drug discovery process before we find out that actually the target doesn’t quite do what we thought it did. If all the validation is done in vitro, often when we get to an in vivo stage, we find that we don’t recapitulate those results”. The opportunity of PROTACs will be that we could validate targets in vivo going forward, something Matthew says will be a huge advantage and he will be discussing in detail at our upcoming Drug Discovery 2018 conference.
Also, in future drug development, the catalytic abilities of PROTACs and the advantages they bring will be explored much more. “With standard inhibitors, if you wanted to switch off a large percentage of a protein, you would need an equivalent large dose of your drug,” Matthew explains. “When using a PROTAC, not only is the protein destroyed, but once the PROTAC is released it is free to target and degrade more and more proteins”. This continuous depletion of proteins means that PROTAC-based drugs could be effective at low doses, potentially reducing the toxicity effects.

Why is a drug discovery career in PROTACs so rewarding?
PROTACs are not typical drugs. They operate outside of Lipinski’s rule of five and offer a stimulating and unique challenge for any researcher. As Matthew says, “with PROTACs, you are not just following a drug discovery rulebook. You are on the cutting-edge of science using all tools available at your disposal to work out how proteins behave and how you could manipulate them.

Book your free place at ELRIG Drug Discovery 2018
If you would like to learn more, or perhaps you’re looking to be at the forefront of PROTACs drug discovery and would like to connect with colleagues and mentors in the field, book your place at our Drug Discovery 2018 conference now. This is the largest event hosted by ELRIG, with an expected 2,000 attendees, making it a fantastic platform for early career professionals and seasoned experts alike to meet and exchange ideas and insights.
The event is open to everyone and registration is free. The conference will be held at the Excel arena in London on October 9th and 10th and is a great way to discover all the very latest developments of this emerging and important technology