Using Click Chemistry to Drug ‘Undruggable’ Tumor Suppressors

I started to collaborate with biologists to help test some of my compounds. This was before the COVID-19 pandemic. I was involved in a project with an infectious disease lab that found some chemicals that could inhibit infection from bacteria that use an enzyme similar to a mechanism that SARS-CoV-2 uses to infect human cells.

Living through COVID-19 made it clear to all of us how urgent it is to move quickly from identifying drug targets to getting treatments to patients.

HMNews: How can you speed up such a complicated process?

Zheng: My work is one part of a big change in the way science is done.

As a graduate student at Scripps Research, my advisor was two-time Nobel laureate K. Barry Sharpless. He shared the 2022 Nobel Prize in Chemistry for his work developing click chemistry, a technique that uses modular components to quickly and efficiently build small molecules. People compare it to building with Legos.

With his guidance, I started to work on developing techniques to adapt a click chemistry reaction called SuFEx so researchers could speed up the process of finding and screening potential drugs.

HMNews: How big a difference does it make?

Zheng: You can go from generating thousands of compounds a year to thousands of compounds overnight. Most will fail, but when you find one that works even a little bit, you can use these same techniques to quickly refine the ones that show potential.

HMNews: How did you go from infectious disease to cancer?

Zheng: Cancer is a challenging disease for doctors and scientists but especially for the people who are sick with it. There is a great unmet need for effective, targeted cancer medicines. After I got my PhD, I spent four years working in the lab of Kevan Shokat at the University of California, San Francisco, focused on the chemical biology of cancer.

One of the things the lab studied was an oncogene called KRAS.

Oncogenes are mutated genes that promote cancer. Since KRAS was first identified as an oncogene in the 1980s, scientists have been looking for drugs that can stop it. Shokat’s lab developed the prototype molecules in 2013 that led to the first targeted therapy to inhibit tumor growth from a KRAS G12C mutation. It was approved by the FDA in 2021, only eight years after the proof-of-concept.

During my fellowship, I developed a small molecule to stop a different KRAS mutation called KRAS G12D.

Just a few years ago, many thought this mutation might be impossible to treat with a drug. The chemistry necessary to hit the target in this molecule was very complicated. But our experiments showed that the solution I found could stop tumor growth in cell models and in mice.

The hope is that this could be the first targeted therapy that can block tumor growth in a form of pancreatic cancer that strikes 24,000 people in the United States alone every year. It’s the most lethal form of cancer, with a five-year survival rate of 8 percent.

HMNews: Why was this mutation so hard to drug?

Zheng: The KRAS protein is basically a smooth ball, with just a few grooves where drugs can attach. People often compare it to the Death Star from Star Wars. The only weak spot is very hard to hit.

Our solution involved changing the way the small molecule finds and binds to that weak spot.

Many drugs fit into a receptor on the target like a key in a lock, and they’re held in place because they fit together physically or by the electrical charge of the two molecules.

There’s another kind of drug called a covalent drug. The molecules of the drug form chemical bonds with the molecules on the target. Once a covalent drug binds, it never falls off, for the lifetime of the target. Some of the most essential drugs — aspirin and penicillin, to name two — are covalent drugs. They offer high degrees of durability, potency, and selectivity.

I discovered a way to make a covalent bond with the G12D mutation.

HMNews: Are you continuing that line of work in your new lab?

Zheng: I’m continuing to use click chemistry to look for covalent drugs for cancer, but I’m switching my focus from blocking oncogenes to trying to repair tumor suppressor genes that have lost their function. There are lots of promising targeted treatments for oncogenes but so far none for tumor suppressors.

Of the top 50 most important mutations in cancer, 13 are oncogenes but 37 are mutations on tumor suppressor genes. These are supposed to be like the brakes that stop a speeding car before it crashes — or in this case, stop cancer from developing. When they fail, it’s bad.

I believe that academic chemists have a responsibility to take on riskier, more challenging projects, and I’ve got some ideas for using covalent small molecule medicines to rescue tumor suppressors from dangerous mutations. I call it covalent restorative pharmacology. That’s what we’ll be focused on in my new lab.

HMNews: Is that shaking things up enough for you or do you have anything else new and different planned?

Zheng: Lately I’ve been studying the chemistry of third and fourth row main group elements. They have unusual chemistry. Most drugs are made with a handful of elements: carbon, hydrogen, nitrogen, oxygen, phosphorus, occasionally sulfur. But nature has given us the gift of 120 elements. I feel obligated to explore the rest of the periodic table to see if there’s anything we’ve missed that could be useful.

I love the chemistry, but what motivates me is the impact this can have on people’s lives.

This interview was edited for length and clarity.