How Belzutifan Became a Cancer Drug

When an ad for a new cancer drug pops up in your newsfeed, it might look like an overnight success. But even developing a seemingly simple daily pill takes a huge coordinated effort, over many years, to come to market.

The kidney cancer drug belzutifan, sold under the brand name Welireg, is a perfect example. Its 30-year journey from a basic biological discovery to an FDA-approved treatment highlights why cancer drug development takes so long, and why it’s worth the effort.

“It’s a beautiful story from bench to bedside, of understanding a basic pathway in human biology and turning it into a meaningful drug. Belzutifan is changing patients’ lives,” said Toni Choueiri, MD, a kidney cancer specialist who has run several clinical trials for the drug. He is the Director of the Lank Center for Genitourinary Oncology at Dana-Farber Cancer Institute and a Professor of Medicine at Harvard Medical School. Dr. Choueiri is a member of the Board of Directors for the American Society of Clinical Oncology (ASCO).

What is belzutifan?

Belzutifan is a targeted cancer therapy that recently made the news for its success in treating clear cell renal cell carcinoma (ccRCC), the most common form of kidney cancer.

It is known as a “first-in-class” drug because it works in a completely new way. The drug blocks a protein called HIF-2alpha. While belzutifan is now advancing kidney cancer treatment, its path started in the 1990s with research into a rare inherited condition called von Hippel-Lindau (VHL) syndrome. VHL syndrome can cause tumors to grow in multiple organs, including the kidneys.

Over the next several decades, researchers evolved their understanding of VHL syndrome and HIF-2alpha and turned it into the novel cancer drug belzutifan.

What is HIF-2alpha?

HIF-2alpha is a protein that helps the body adapt to low oxygen. When oxygen levels drop, HIF-2alpha acts like an emergency switch. It pairs up with a partner protein to turn on genes that build new blood vessels and promote cell growth and survival.

When oxygen levels return to normal, a cellular monitor called the VHL protein helps tag HIF-2alpha so it gets broken down. But if the VHL monitor doesn’t work, as in VHL syndrome, HIF-2alpha builds up. It continuously signals for new blood vessels and growth factors, which can feed and grow cancerous tumors.

Much of the early research into VHL, HIF-2alpha, and cancer was led by Dr. William G. Kaelin Jr. at Dana-Farber Cancer Institute and Sir Peter J. Ratcliffe at Oxford University. Their work was so foundational to understanding how cells sense and adapt to oxygen that they, along with Gregg L. Semenza, earned a Nobel Prize for this research in 2019.

How was belzutifan developed?

Knowing that HIF-2alpha can drive cancer growth in people with VHL, researchers started working on developing a drug to block the protein. Most drugs work like a key fitting into a lock on a protein, but HIF-2alpha appeared to have a smooth surface. It looked like there was nowhere for a key to go.

After years of study, researchers at UT Southwestern identified a potential lock on the protein. A hidden pocket in HIF-2alpha could be targeted with a drug to unlock it. Their colleagues helped launch a small biotechnology company to design a key that fit the protein just right. Belzutifan is that key.

How does belzutifan work?

Belzutifan works by slipping into the hidden pocket on the HIF-2alpha protein. It changes HIF-2alpha’s shape so the protein can no longer attach to its partner protein. When this happens, it doesn’t turn on growth and survival genes. Without signals to build a blood supply or multiply, the cancer cells and tumor stop growing.

Unlike traditional chemotherapy, which kills many fast-growing cells, including normal cells, belzutifan is more targeted. It is highly specific to the protein driving the cancer’s growth. Blocking that protein slows and stops tumor growth while sparing most healthy cells.

Clinical trials for belzutifan

Once researchers had this drug, it needed to be tested in people. Recognizing belzutifan’s promise in early clinical trials, a large pharmaceutical company bought the small biotech firm that pioneered the drug. The company then used its resources to complete large global studies.

After assessing the data from those studies, the US Food and Drug Administration (FDA) approved belzutifan to treat cancers caused by VHL syndrome. But the research didn’t stop there. Knowing that most common kidney cancers share the same genetic glitch as VHL syndrome, the pharmaceutical company launched additional trials. Dr. Choueiri and others presented some of the results at the 2026 ASCO Genitourinary Symposium.

The FDA has since expanded the drug’s use to treat ccRCC. Belzutifan can be used when kidney cancer has spread to other parts of the body. It can be given in combination with the immunotherapy drug pembrolizumab after surgery to help stop the cancer from coming back. The drug can also treat certain tumors on the adrenal glands, which are small glands on top of the kidneys.

This novel cancer drug was made possible by the dedication of everyone involved, with each contributor paving the way for the next breakthrough. “What makes belzutifan exciting is that the whole research community was integrated,” said Dr. Choueiri. Because of stories like this one, scientists will keep looking to turn the next challenging target into a lifesaving medicine.

Learn more about cancer treatments from the American Cancer Society:

• Treatment Types
• Understanding Your Options for Cancer Treatment
• Understanding Information About New Cancer Treatments

Dr. Choueiri is a member of ASCO’s Board of Directors.