Ziyang Zhang’s drug discovery journey

Photo courtesy of Ziyang Zhang

By Marge d’Wylde

The College is pleased to welcome Dr. Ziyang Zhang who will be joining us this summer as an assistant professor in the Chemistry department in the areas of chemistry and chemical biology. Ziyang is coming from a postdoctoral appointment with Professor Kevan Shokat at the University of California San Francisco (UCSF) where he has been focused on research devising ways to drug mutant forms of KRAS, a protein commonly implicated in cancer. He also created a new strategy for recruiting the immune system to attack cancers with the G12C mutation and devised a new method for selectively delivering kinase inhibitors into the brain while minimizing side effects in the rest of the body. 

Ziyang grew up in Taizhou, China. He describes it as a lovely small city on the east coast. “I would say it is a very cozy city,” Zhang comments. “I had a lot of fun there as a child. My parents still live there. When I was in sixth grade, I discovered I really liked computers and was good at coding. We didn’t call it coding back then. Instead, we used the phrase ‘computer interest club’. It was a little bit about learning to write code, but it was also a little bit about playing video games without other people knowing about it.”

Mentors were very important to Ziyang. “Ligang Ni was my wonderful mentor in high school. He really got me interested in chemistry. He would do some crazy experiments that were just cool…high school kids cool”, Ziyang states. “He was unique. It is very painful for a lot of high school students to study science in China because the way our curriculum is constructed it involves a lot of memorizations without understanding the underlying science. But his approach was totally different somehow. He just made it fun. But there was science behind it too.”

Ziyang went on to double major in chemistry and computer science as an undergraduate at Peking University. “It’s interesting that there is a creative practice in common between coding for computers and chemistry discoveries. You are developing something completely new that hasn’t existed before,” he comments.   

During Ziyang’s second year he was introduced to autoimmune diseases because of a family member. “I was fascinated that the body’s immune system does not know what to do and decides to destroy itself. Why would it do that? And then I started to learn about organic synthesis and these natural products that are immune suppressants. And that became very interesting.”

Ziyang went on to graduate studies at Harvard in the lab of Andrew Myers. As a first-year student he was introduced to a project to devise a general strategy for the total synthesis of macrolides, a class of well-known and widely used antibiotics with complex structures. Traditionally these antibiotics are made by modifying naturally derived macrolides—an approach that limits the potential diversity of new molecules. “They are not trivial to make from scratch,” Zhang says. But he found a way to do it.

Ziyang co-led a team that divided macrolides into eight generic parts. By making several varieties of each of those eight parts and then stitching them together in different combinations, the team created hundreds of new macrolides. Many of them showed promise at killing bacteria resistant to commercial macrolides, and the work, published in 2016, formed the basis of a company called Macrolide Pharmaceuticals, now Eloxx Pharmaceuticals.

After Harvard, Ziyang joined Professor of Chemistry and Cellular and Molecular Pharmacology Kevan Shokat’s lab at UCSF for his postdoctoral work. During his five-year appointment, Ziyang has done research in multiple areas focusing on ways to drug mutant forms of KRAS, a protein commonly implicated in cancer.

Shokat’s lab had developed a small-molecule inhibitor of KRAS G12C, a mutant in which a glycine has been replaced by a cysteine. But a form of the protein in which the same glycine is replaced by an aspartate—a G12D mutation—had proved particularly difficult to drug. The mutation is frequently found in pancreatic cancers. Ziyang discovered a new G12D inhibitor. The discovery is timely because doctors have recently seen tumors develop resistance to G12C inhibitors. Shokat says the approach “could lead to cures” for some cancers. Zhang hopes to generalize the strategy and apply it to other proteins beyond KRAS.

“I am looking forward to starting at UC Berkeley”, Ziyang states. “I am very interested in continuing to explore autoimmune diseases. I feel I now have the tools to research ways we can use small molecule chemicals to change how our T cells work. Our T cells are amazing. They are constantly checking on nearly every cell in the body. But they can make mistakes which can lead to certain autoimmune diseases. One of the areas of exploration that we will be researching in my lab is ways to help with antigen presentation of cancer finding ways to block the presentation of disease associated antigens. That hasn’t been done with chemical approaches before.”