Carlos Velazquez

Carlos Velazquez is a Professor in the Faculty of Pharmacy & Pharmaceutical Sciences at the University of Alberta. His research group is developing proteolysis-targeting chimeras (PROTACs), focusing on optimizing selectivity toward oncogenic forkhead box (FOX) transcription factors.

How did you get into your area of research?

This dates back a few years (1993), when I was an undergraduate chemistry student at the University of Guadalajara. At that time, the small Chemistry department didn’t have a single PhD teaching in the classroom until a recently hired professor with a PhD in medicinal chemistry returned to the university and started setting up a research lab, which naturally attracted the attention of not only his colleagues but also students. When I heard about the possibility of creating novel drugs for untreatable or incurable diseases, I was immediately drawn to it. I registered with him because he was looking for students to work on a brief research project. That's how I got into research: I had a good role model—someone with the expertise and vision to start a research program where there was none.

Please explain your research.

As part of the larger field of targeted protein degradation (TPD), I am developing new drug molecules known in the literature as proteolysis targeting chimeras (PROTACs) that can eliminate FOX proteins involved in pathogenic processes and abnormal biochemical pathways.

My research group targets proteins in a large family of transcription factors called forkhead box (FOX) proteins. Some FOX family members are oncogenic while others are tumour suppressors. The challenge is developing drug molecules that only induce degradation of oncogenic FOX proteins while sparing tumour suppressor FOX proteins.

PROTACs are made of 3 main components. One component binds the protein of interest we want to degrade; another binds specific enzymes in the body called E3 ligases; and the third component bridges the two. When PROTACs enter cancer cells, they bind to the protein of interest, which is then tagged with ubiquitin and degraded.

We have developed experimental drug molecules that induce FOXM1 degradation, which is heavily involved in cancer development. Almost all cancers require FOXM1 because it's essential for cell replication.

We currently have three lines of investigation in my lab: (a) design, synthesis, and screening of PROTACs selective towards oncogenic FOX proteins, (b) correlating the water solubility/cell membrane permeability of PROTACS with their in vivo potency, and (c) establishing what types of cancer these drugs are more effective against.

What impact is your research making or do you hope it will make in the future?

I aim to determine whether FOX transcription factors are suitable clinical drug targets. I used to be a little bit naive and say, “I'm going to create a new drug molecule,” “I'm going to patent this,” “I'm going to move it all the way to clinic.” The older I get, the more I realize that developing drug molecules is not only a very long enterprise, but a very expensive one. Pharmaceutical companies have entire teams and multi-billion-dollar budgets, all focused on developing a single drug molecule that, 10 or 15 years down the road, may or may not be in the clinic. Competitively speaking, I often ask myself, “What can I do with a much smaller budget?” I'm satisfied if I contribute to generating and sharing knowledge that clarifies the importance and relevance of FOX transcription factors in human diseases, and if a company picks it up and moves it forward.

Where do you see your area of research going in the future?

I think PROTACs may one day become mainstream treatments in the clinic and be used not only for cancer, but also for other diseases. Any disease that involves protein expression could be treated with PROTACs.

Which elements of your work do you find the most rewarding?

Working with students. Seeing them learn new techniques, gain new knowledge. Having interesting discussions with enthusiastic, bright young minds. Most of the time, at least some of us like to brag about our ideas. But when we think about it, often those ideas - the ones that we publish and the ones that we compete for research funding - come from students and postdocs. Someone with a fresh mind who thinks of things that we otherwise might not have thought of. I think this is an often-overlooked aspect of our work.

What research challenges are you facing?

The biggest challenge is a lack of sufficient and timely funding. Working hard with a very low success rate with granting agencies is something all researchers face. Also access to funds to repair and upgrade research equipment. Another challenge is a lack of local students. This is probably a particular issue some of us face in the Faculty of Pharmacy & Pharmaceutical Sciences, as most pharmacy graduates don’t want to pursue a research career. We lack qualified students interested in research, so we have to recruit students from other faculties or other countries, which is not always easy.

What are you looking for in potential collaborators?

I'm always looking to collaborate with anyone with expertise in drug screening using animal models or 3D cell models. Also, anyone developing a vehicle, nanoparticle, or micelle that could help us get these drugs into solution and then into cancer cells.

I'm open to helping or participating in any research program where a CRINA member thinks PROTACs could be useful.

What is your main piece of advice for graduate students?

My advice is to pursue graduate studies only if you're passionate about it and truly believe in what you want to pursue. Look for a supervisor with whom you feel synergy, because it's really hard to start a new degree without it. Networking is most of the race; if we network effectively, we can advance our careers. And be mentors, because we don't learn something until we teach it.

If you hadn't become a researcher what would you be?

I'd probably be working as a pharmacist in a government institution back home, or maybe in a medical lab, because back then our education was multidisciplinary. We received instruction not only in pharmacy, but also in food analysis and clinical specimen analysis. Unlike in Canada, pharmacists in Mexico aren't really involved in treating patients. They're more involved in quality control in drug production. So, I might have worked for a pharmaceutical company doing quality-control analysis of drug molecules. One of those paths, I'm not really sure.

What's one thing people may be surprised to learn about you?

When I finished my M.Sc. in medicinal chemistry in 1997, a group of ‘entrepreneurs’ approached me with a research project involving the chemical synthesis of amphetamine derivatives for veterinary use. The money they offered was really good; for any young graduate with student loans, it would have been the perfect opportunity to make money doing what I was trained for. However, the more I discussed the project with the company, the more I realized it was likely part of a well-organized scheme to obtain illegal substances. A few months after I turned them down, my suspicions were confirmed when I read about police raids and arrests related to this experience. It was a really close call.

How has CRINA helped support your work?

I appreciate the highly collaborative environment CRINA promotes because we cannot do everything by ourselves. We need the collaboration, advice, and guidance of all the researchers and investigators who help us.