“While scientists have made great strides in understanding the human genome, our understanding of human genetics hasn’t been effectively translated into new therapeutics,” says Xiaoyu Zhang, Assistant Professor of Chemistry at Northwestern and member of the Chemistry of Life Processes Institute. “We pretty much know what genetic alterations are associated with what diseases, but in terms of therapeutics, there’s a huge gap.”

In fact, Zhang explains, only a small fraction of approximately 5,000 disease-related proteins are considered “druggable” with small molecules.  Zhang’s lab is interested in finding more ways to target currently undruggable proteins using a combination of proteomics and functional genomics with an approach known as ligand-induced protein degradation.

Proteins are responsible for a variety of cell functions. They play important roles in maintaining signaling transduction, gene transcription, enabling different cells to communicate with one another, and other functions. Some proteins, such as enzymes and receptors, typically have hydrophobic pockets that scientists have found ways to target with small molecules.

“There are many disease-related proteins like transcription factors and adaptive proteins that do not have these hydrophobic pockets, making conventional small molecule drug discovery really challenging,” says Zhang.

Over the past decade, a compelling approach for attacking ‘undruggable’ protein mediators of disease has emerged.  This approach, ligand-induced protein degradation, is based on  targeted elimination of disease-causing proteins from cells by directing these proteins to the ubiquitin-proteasome system, or UPS, which is a multi-enzyme machinery used by cells to clear short-lived, damaged and misfolded proteins. This strategy functions catalytically and more importantly has also been demonstrated to target historically ‘undruggable’ proteins, such as transcription factors and RNA splicing factors. Several therapeutics on the market, or currently in clinical trials, are based on this mechanism of action.

“Our mission is to use chemical biology approaches to discover small molecules that hijack UPS in the cells to degrade more disease-causing proteins, particularly those undruggable proteins,” he says.

Zhang’s lab hopes to tackle a range of human diseases, starting with cancer (he is a member of Northwestern’s Robert H. Lurie Comprehensive Cancer Center), then autoimmune diseases, neurodegenerative disorders, and many more disease areas.

Zhang completed his BS in pharmaceutical sciences and MS in bioanalytical chemistry at Zhejiang University in Hangzhou, China, and earned his PhD in biochemistry and molecular biology at Cornell University in 2017. After four years as a postdoctoral associate at Scripps Research, he became an assistant professor at Northwestern in February of this year.

Zhang says his CLP membership and faculty interactions are very important for his research program. His CLP collaborators include CLP director Neil Kelleher, Karl Scheidt, Shana Kelley, Nathan Gianneschi, and others in the Feinberg School of Medicine.

One of his graduate students is a recipient of Chemistry of Life Processes NIH T32 traineeship, which will enable her to gain training and experience in both the chemical and biological aspects of drug discovery.

Xiaoyu Zhang, Assistant Professor of Chemistry, in his lab with graduate students Ananya Basu (left) and Isabella Riha (right).

“This is a big deal to the student because she can benefit from the support and explore high-risk, high-reward projects,” says Zhang. “I’m really grateful CLP has this program to support students who are interested in chemical biology research.”

Story and photo by Lisa La Vallee