The hole in a protein that led to a cancer drug

Much of science and public health is invisible, and that needs to change. This series brings you stories to illustrate these benefits through the voices of scientists, patients, and public health workers. This is the second story in the series, you can read the first one here.

If you have a story you think I should tell, reach out at sciencewhizliz@gmail.com.

Not too long ago I picked up the phone and found out my father has clear cell renal cell carcinoma, abbreviated “ccRCC”. It’s the most common type of kidney cancer and it can be highly aggressive. This isn’t news anyone wants to hear about a family member. He’s still undergoing treatment and his prognosis is uncertain.

Then, recently, I sat down to talk to a colleague about the research he has done — and how it led to the development of a drug for, believe it or not, ccRCC.

I wanted to tell you the story of this drug even before I knew about this personal connection. It’s another powerful reminder of what research can do. Now, the person who helped make me may eventually benefit from this medication. You can bet I’ve already notified him and his wife about the work I describe here, to make sure they find out whether it’s an option for my dad.

So let me tell you a little bit about its origin story.

Dr. Kevin Gardner* was working in his office when two postdocs came knocking at his door with pure excitement.

“You need to come see this graphic right now,” he remembers them saying.

So he did.

Gardner is a structural biologist, which means he spends a lot of time studying the molecular shapes of proteins. This is important, because as I’ve told every biology student I’ve ever taught: structure dictates function.

What does that mean?

Think about it. A fork wouldn’t be so great for eating soup, would it? But a spoon is perfect. The shape of these two instruments dictates what jobs they can do. The same is true for proteins, which are the building blocks of nearly everything in our bodies. The shape a protein takes dictates what job it does. When that shape changes, like maybe because of a DNA mutation, the protein can’t do its job properly. This can contribute to disease.

So that day, Gardner and his team discovered that a protein they were studying, known as HIF-2α, had a hole in the middle of it. In proteins, holes usually mean something else binds there — think of it like a lock waiting for a key. No one had seen this before, so the discovery opened up a whole new area of research.

Human cells, like many cells, need to be able to sense oxygen levels. Too little oxygen, and the cell needs to respond and redirect resources to adapt. The program that controls this is called the hypoxia-inducible factor, or HIF. HIF is not unique to humans — mice, fish, worms, and flies all have similar components. When something is conserved across so many types of organisms, it’s usually because it’s critical for survival. HIF-2α is one component of this system.

Under normal oxygen conditions, a protein called VHL helps keep HIF-2α in check and triggers its destruction. But in some cancers, VHL doesn’t work correctly. Without properly functioning VHL, HIF-2α builds up. This build up can cause it to switch on genes that drive tumor growth and give cancer cells an advantage. We see this happen in von Hippel-Lindau disease, which is caused by a mutation in the VHL gene that stops it from working. People with VHL disease develop cancerous and non-cancerous tumors in different parts of the body, including the kidneys.

Proteins that turn genes on this way are called transcription factors, and for a long time scientists believed transcription factors were undruggable (aka no good way to turn them off with a drug). This is why the discovery that HIF-2α had a hole in the middle of its structure was so significant. That hole provided an opening for developing drugs that could stop HIF-2α from functioning.

Once Gardner’s team discovered this opening within HIF-2α, they began screening many small molecules to see which ones could fit into it and disrupt HIF-2α’s ability to function normally.

Eventually, thanks to a team effort that included collaborators from other university labs, they found a molecule that did exactly that. They also eventually showed it could help stop HIF-2α from working in cancer cells.

Their research now had the potential to one day help patients.

In the early years of this project, a postdoc in Gardner’s lab was working to keep this research going. He applied for a fellowship from the American Cancer Society that would provide about $150,000. The science was promising but unproven. It could work, or it could fail.

The American Cancer Society scored the proposal in the middle bin. Not a yes, not a no. Instead, they passed it to their local chapters in Dallas and Fort Worth and asked whether either one wanted to fund it.

Fort Worth said yes, and they funded the fellowship through donations in the $5,000 to $10,000 range.

“Those early monies were absolutely critical for this project to be able to take flight,” Gardner said. “I love the genesis story of it coming out of people who might be mothers, fathers, brothers, or sisters of a cancer patient.”

Eventually, the project attracted NIH grants, then a high-throughput facility to test hundreds of thousands of compounds (to find ones that would disrupt HIF-2α) , then a network of collaborators across biochemistry, cancer biology, and medicinal chemistry. This success in university labs led to private funding and a new startup company called Peloton Therapeutics. Peloton eventually grew to about 70 people, and developed new HIF-2α inhibitor compounds that went through Phase 1 and Phase 2 clinical trials.

Peloton was bought by Merck in 2019, and Merck took one of the inhibitors Peloton was working on – originally called PT2977, but then renamed belzutifan (aka Welireg) through additional clinical trials. Eventually it made it to market where it can now be prescribed to patients.

The FDA approved belzutifan in August 2021 for patients with VHL disease-associated tumors, including kidney cancer, certain pancreatic tumors, and tumors of the central nervous system. The results in these patients have been remarkable. In clinical trials, nearly 70% of VHL patients responded to the drug, with some seeing improvements that lasted over four years. Patients who previously needed frequent surgeries saw the number of required procedures drop significantly.

In 2023, the FDA approved belzutifan for a second use: advanced ccRCC in patients whose cancer had progressed after other treatments. In May 2025, a third approval came for patients with pheochromocytoma and paraganglioma — rare adrenal gland tumors also driven by the HIF-2α pathway. Most recently, the FDA approved its use in combination with another cancer therapy called Keytruda (pembrolizumab) for ccRCC. Early data suggest that combining belzutifan with other treatments may improve outcomes further.

When researchers begin studying something, they don’t know whether it will ever pay off. Much research fails before it leads to a treatment. And sometimes, the answers to whether these really will payoff or not takes a long time – in this case, about 20 years from Gardner’s first data exploring the shape of this oxygen sensing molecule to an FDA-approved drug. But through every failure along the way, we learn valuable things that help contribute to future successes.

Academic labs take on this foundational, high-risk work. Startups bridge the gap to clinical trials. Large pharmaceutical companies have the manufacturing capacity, distribution networks, and capital to bring a drug to patients at scale. The ecosystem that turns scientific discovery into new treatments requires all three — and at every stage it requires stable, sustained funding.

Gardner keeps three things on his wall: an early printout of that structural data with a postdoc’s handwriting on it, a sign from Peloton’s opening barbecue in Dallas, and an award from The Biophysical Society recognizing the project’s contribution to health and disease. The dates span more than 20 years.

“If I knew everything I know now,” he said, “maybe I could shorten the timeline by four or five years. But science takes time and investment to build the teams of experts and the foundation of knowledge to do something big like this.”

Belzutifan is now a real drug, used by thousands of real patients. For the patients who qualify, it represents a genuine transformation in available options.

And the science hasn’t stopped. Researchers are now studying next-generation HIF-2α inhibitors designed to overcome resistance, new combinations with immunotherapy, and entirely new approaches to targeting HIF.

This is the invisible infrastructure of medical discovery: a structural biology lab noticing something unexpected, a postdoc writing fellowship applications, donors in Fort Worth giving what they could, and a pharmaceutical company working to get the drug across the finish line.

“Scientific discoveries really do require this whole ecosystem,” Gardner said, “and stable funding along the way.”

The problems science must tackle are many. The tools exist and are being developed every day. Scientists are ready.

The question is whether we are willing to keep investing in the research — at every stage — to make future treatments both possible and better.

For my father, and for everyone else who may one day need what started in a lab, I hope the answer is yes.

Science is still under attack in the U.S. which harms our ability to keep doing work like this. We can all do what we can to help. Some ideas:

• Read more about the new proposed rules that will make it harder to fund research like this here, and consider submitting a public comment. It’s not too late.

• Contact your elected officials and let them know you want science supported!

• Shares stories, like this one, that help people see the ways in which science benefits us.

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*Thanks to Dr. Kevin Gardner for sitting down with me to tell me this story, and his role in it.

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