Fighting Cancer via PROTACs, RIPTACs, and the Downmodulation of a Transcription Factor

Professor Craig Crews during the interview session. Credit: The Habibat Project

PROTACs (PROteolysis TArgeting Chimeras) were first introduced in 2001 to help remove specific unwanted protein growths, with the potential to target and destroy disease-causing protein tumors. This technology now presents a promising alternative to chemotherapy and precision medicines where tumor cells can develop resistance systems. 

There have been notable developments of the technology by several companies in the race to transform it to a usable drug. Notable amongst them is Arvinas Therapeutics, a company founded by Craig Crews, Professor Of Molecular, Cellular, and Developmental Biology at Yale University, whose PROTACs technology is in the third phase of development for breast cancer treatment and underwent human trial for the treatment of prostate cancer in 2019.

Despite the organization’s significant advances, Crews, who is also this year’s IUPAC-Richter prize winner in medicinal chemistry, along with his research teams, has continued to make strides, further publishing a “proof-of-concept” study on downmodulating the transcription factor, brachyury, to help eliminate chordoma, while also working on the development of Regulated Induced Proximity-Targeting Chimeras (RIPTACs) through another company, Halda Therapeutics.

Speaking to The Habibat Project, he sheds more light on all stages of these developments.

(This interview has been edited for length and clarity).

How do you feel being the recipient of the 2024 IUPAC-Richter prize in medicinal chemistry?

Well, I'm very honored to be recognized and excited for the potential impact that this technology [PROTACs] will have on the field of drug development.

What is the rationale behind the PROTACs drug development?

These molecules are the product of many years of optimization. One of the hopes for this technology is that by being catalytic in terms of its mechanism, one would not need to dose at the multiples necessary for an occupancy-driven approach. So if you think about a drug target and a drug, if it binds, you get the clinical benefit, [and if] it falls off, you have the disease. And since most drugs do not bind permanently, it means that if you have a drug that falls off, you have to have another drug and another drug [multiple doses of drugs]; you have to have all these extra drugs around to make sure that at any given time, you have occupancy. And that requires excess drugs. That's one of the main challenges today in drug development; how do you achieve excess high levels systemically of your drug?  It's not only the challenge in achieving and maintaining those concentrations, but it also means that excess [concentration] has the potential to start hitting other drug targets. And that's where the side effects come in. If we have a catalytic drug whereby the paradigm is not occupancy but events, and the events are binding, tagging, elimination, binding, tagging, and elimination, [then] it's event-driven pharmacology. That is catalytic and if you can have multiple rounds of recruiting and tagging, then one could get away with less drug, and less drug has the potential to have different pharmacokinetic pharmacodynamic relationships, as well as the potential for maybe fewer side effects.

What is the most recent update to PROTACs, and in what way does it change what is already known about it?

Yes. Arvinas, the company I founded in 2013, now has four compounds that will be going into the clinic. Three of those compounds are focused on oncology targets. But the fourth is a neurodegeneration target. And what is particularly exciting about that target is that it is believed to play a role in Parkinson's disease. And the important part for the PROTAC technology and its role in drug development is that this particular PROTAC candidate from Arvinas is not only orally bioavailable like all the other four, the total four, at Arvinas, but this also crosses the blood-brain barrier. So, the potential to be able to get a catalytic protein degrader molecule like PROTACs into the brain really opens up new areas for drug-target exploration, and new indications like neurodegeneration. That's something that Arvinas is really pioneering. They're farthest along in their breast cancer indication and are in phase three trials now with anticipated top-line readout at the end of this year in terms of the results of that trial. But I should also say there are many other companies that are making important strides in PROTACs development.  

You, along with some other authors, published a study last month on downmodulating the transcription factor brachyury. Can you explain this for non-scientists in plain easy-to-grasp English?

Sure. Brachyury is a protein that is turned on during human development. In fact, it makes our spinal cord when we're embryos, then gets turned off. After you make the spinal cord, you don't need another spinal cord, right? You only need one. The problem is that patients – human adults – can reexpress this one gene, brachyury, and the cell tries to make a spinal cord. And that cell becomes a particular type of cancer called a Chordoma. More than 90% of patients that have Chordoma have a reexpression of this gene that should be silenced and was useful for making the spinal cord. You don't need a second spinal cord. If we could drug the brachyury, we'd be able to help these patients with chordomas. My lab has shown that a particular small molecule can covalently permanently bind to brachyury, leading to its downregulation. Hopefully, in the future, this strategy could be used to treat Chordoma patients.

How soon can this translate to a drug that would help destroy Chordoma growth?

There is a patient advocacy group, the Chordoma Foundation, that is led by an amazing young man named Josh Summers, who is a Chordoma patient himself. Josh Summers and the Chordoma Foundation have taken a very proactive approach to bring together academics, [the] pharmaceutical industry, drug developers, [and] the regulatory agencies to see how the foundation can help accelerate this work. Together with another foundation called the Mark Foundation, they have been instrumental in pushing forward and supporting our work with a brachyury potential drug.

Who funded the research?

The Mark Foundation, the Chordoma Foundation, and the NIH, [the] US National Institutes of Health.

Are you working on new research that is likely to have a drastic effect on the public well being?

There is a technology that I started with Halda Therapeutics [Crew’s third company], and it is a hetero-bifunctional drug like PROTACs, where you have two ligands on either side and a linker. But it's not degradation. Let me set this up in terms of what it is helping; if you think about cancer and cancer drugs, chemotherapy was revolutionary in the 40s and 50s because, up until then, doctors really did not have a way to address fast growing tumors. But chemotherapy is a bit of a sledgehammer, in the sense that it just kills everything that's growing. And that's why in the 80s and 90s, precision medicine really was a major advance where we knew the problem proteins, the kinases, and we developed drugs for those targets. But where we are now is that there are many ways the tumor cells can evolve resistance mechanisms to these precision medicines. What we really need is a way to address all of these different resistance mechanisms in a global way. Because you can have one precision medicine drug, but many different resistant mechanisms. As a result, what we've come up with is this top technology we call RIPTACs [Regulated induced proximity-targeting chimeras]. 

The idea is that we want to kill selectively, just the tumor cell, whereby, if you take animals that are growing a human tumor for prostate cancer, if untreated, the tumor continues to grow; if you treat with the standard of care Enzalutamide, the tumor doesn't care anymore; but if you treat with the RIPTAC, now the tumor doesn't grow at all. In fact, it looks like it might even start to regress, and it's because of this complex between the essential protein and the tumor-selective protein. I hope that gives you an idea of the next technology that I think is going to be very exciting. 

How exactly would you say this particular technology compares to the others currently available to fight malign tumor growth? 

This is a new approach that offers new possibilities. If you think about one area that's very exciting these days in drug development is antibody drug conjugates, ADCs. ADCs work by having a toxic molecule conjugated to an antibody that will bind to a specific protein on the surface of a tumor cell. Upon binding, it gets internalized, the toxin is released, and you get selective delivery of a toxic protein to the tumor cell. But that's only through recognition of something uniquely expressed on the outside of a tumor cell. A RIPTAC can be considered an intracellular equivalent of an ADC, in the sense that they're taking advantage of the overexpression of an intracellular target tumor selective protein and using that tumor-selective protein to now become part of the inhibitor of an essential protein. So, we can selectively target cell death in tumor cells using the recruitment of this tumor-selective protein to now kill those tumor cells. So it opens up new areas to exploit differential expressions, not on the outside of the cell, like the antibody drug conjugates, but using intracellular differences of proteins between normal cells and tumor cells.