Ann Nguyen:

Hello, my name is Ann Nguyen, Senior Associate Conference Producer at Cambridge Healthtech Institute. Today, we have a special podcast for the upcoming Targeting the Ubiquitin Proteasome System conference, September 26-27, part of the 15th Annual Discovery On Target event in Boston. We're very excited to have joining us by phone Dr. Craig Crews, Professor of Molecular, Cellular and Developmental Biology as well as Chemistry and Pharmacology at Yale University. Dr. Crews is a pioneer of the rapidly emerging strategy of modulating proteostasis and we're certainly delighted and honored to have him join us today.

Craig, thank you for joining us.

Craig Crews:

My pleasure.

Ann Nguyen:

The ability to target components of the ubiquitin proteasome system with bifunctional PROTACs molecules has recently generated significant interest within the drug discovery community. Can you share with us a bit about the history and progression of this new mode of drug action?

Craig Crews:

Sure. My interest in this field stems from a longstanding interest in the field of controlled proteostasis, the idea of controlling protein levels inside a cell using a small molecule approach. Initially my lab was focused on blocking degradation, development of novel proteasome inhibitors, one of which we see the approval and is now sold as KYPROLIS.

But, in 2001, together with collaborator Ray Deshaies, we published the first report of a bifunctional molecule that can hijack E3 ligases and recruit target proteins that would not normally be recognized by the E3 ligases and cause those target proteins to be ubiquitinated. This initial PROTACs as we call them, proteolysis targeting chimera, were peptide-based. But it was clear after several demonstrations of proof of concept that to move this further that we need to go into the small molecule arena. My lab developed the first small molecule-based PROTAC, a nutlin-based PROTAC that targeted androgen receptor recruitment to the E3 ligase MDM2. That was in 2008. But, it was clear that nutlin was not going to be a very robust recruiting element for PROTAC.

In 2009, my lab made a decision to focus on replacing what was a peptidic portion of our early first-generation PROTACs with something that was small molecule, a VHL small molecule. All of the excitement that is around the field of induced protein degradation now as a therapeutic strategy really derives from that decision to now make these PROTACs more drug-like because if we had not decided to do that, I'm confident that PROTACs would have died a very quiet death as a chemical biology curiosity. But since that decision, we now have PROTACs that have better pharmaceutical properties and this generates a lot of excitement, a lot of new labs are now working on. There's new companies as you know and hopefully new drug candidates will be entering the clinic soon.

Ann Nguyen:

There are several commercial entities currently working on a new generation of bifunctional molecules including Arvinas, a biotech you founded. Can you discuss some of the current challenges surrounding this approach during preclinical development?

Craig Crews:

Sure. I should point out that there are a lot of advantages to the technology in terms of the targets that can be degraded. My lab and others have shown that cytosolic proteins, membrane-bound proteins, nuclear proteins, all can be recruited through E3 ligases, ubiquitinated and destroyed by the proteasome. But there are some proteins that can't be treated or targeted with this approach and those being secreted proteins, proteins that are in the secretory pathway in which there is no E3 ligase accessible. I should emphasize that not all targets are PROTACable, if you will. But the bigger challenge has to do more with medicinal chemistry and these are generally large molecules ranging in size between 800 and 1,200 daltons. They have nontraditional pharmaceutical properties that need to be addressed.

Ann Nguyen:

You are chairing a session and giving a keynote address during the upcoming Targeting the Ubiquitin Proteasome System conference, September 26-27 in Boston. Can you share with us a bit on what you hope to convey during the session and keynote lecture?

Craig Crews:

Yeah, I hope to be able to set the stage in terms of providing historical context to the field having worked on this now for 16 years but also to introduce some of the very exciting talks that we're going to be hearing. I'm very excited the fact that there are a variety of presentations from both academic as well as commercial labs that are targeting a variety of different targets, target proteins, as well as hijacking a variety of E3 ligases. It really shows the breadth of this nascent field well.

Ann Nguyen:

We would like your opinion on the future of PROTACs which appears to be very promising. You've talked about some of the current challenges but can you share with us how you're working to address and overcome these challenges for continued development?

Craig Crews:

Yeah. The challenges fortunately are addressable using a variety of known techniques in the medicinal chemistry community. But I feel that the promise of this technology is quite strong. The opportunities to be able to target undruggable proteins, proteins that are transcription factors, scaffolding functions that are currently undruggable now hopefully will be addressable using a PROTAC technology. I liken this technology to a chemical equivalent of RNAi or CRISPR but yet not having the same pharmaceutical challenges in terms of developing those nucleic acid-based approaches into viable therapeutics. I think that moving forward we're going to have a variety of new drug targets that heretofore have not been druggable and I believe that there are going to be a new emphasis on simply finding binding ligands to proteins with the idea that even those ligands may not have any biological activity upon binding the target protein, those ligands can be converted into a PROTAC and cause those proteins to be degraded. I'm very optimistic about the future of the field.

Ann Nguyen:

For those listening, explore the Discovery On Target website for additional information. Thank you for tuning in and we look forward to seeing you at the conference. Goodbye!