Making cancer fight itself: The promise of PROTACs

Proteolysis-targeting chimeras, or PROTACs, are a new area of research in medicinal chemistry; they can leverage cancer cells’ own protein degradation machinery to target cancerous proteins.

Courtesy of Jianchao Zhang

Jianchao Zhang received a JBC/Tabor award for his paper about designing a proteolysis-targeting chimera that inhibited tumor growth.

Jianchao Zhang, a research assistant professor at Southern University of Science and Technology, or SUSTech, has always been interested in the mechanism underlying cancer development, and he became intrigued by PROTACs after learning of their potential while working in Hai Rao’s lab. Zhang and his colleagues recently discovered a PROTAC with the potential to treat chronic myeloid leukemia, a type of blood cancer.

“PROTACs are one of the most promising technologies in the biomedical field today and offer significant advantages in overcoming drug resistance and targeting undruggable targets due to their unique design and mechanism of action,” Zhang said.

In the beginning, Zhang worked primarily on cancer biology and metastasis. In 2020, Rao moved from San Antonio, Texas, to SUSTech in Shenzhen, China, where Zhang joined his lab. Zhang and colleagues began searching for chemists to collaborate with to synthesize their PROTACs. A year later, they found Lijing Fang from the Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, whose expertise in synthetic chemistry enabled them to embark on their PROTAC project in 2022.

Zhang’s journey with PROTACs was not straightforward. His team tried to target other cancerous proteins for PROTAC development, including one involved in lung cancer but encountered many obstacles.

“PROTACs are easy to design but hard to predict the outcome,” Zhang said.

After altering their design approach, they successfully developed their PROTAC, Arg-PEG1-Dasa, which can degrade the cancerous protein BCR-ABL in chronic myeloid leukemia. For the paper in the Journal of Biological Chemistry describing this work, Zhang received a JBC/ Herb Tabor Award.

What’s next for Zhang’s lab? Optimizing chemical structure and protein degradation is a critical part of drug discovery.

“We are interested in exploring the effects on (protein) degradation efficiency and rate by other amino acids,” he said. “Additionally, linker optimization is crucial for PROTACs, and we aim to modify linker types to further enhance this single amino acid PROTAC.”

Zhang and his colleagues are also working on designing PROTACs to target different types of cancer and making their PROTACs smaller to improve cellular uptake.

No FDA-approved PROTACs are yet on the market; however, several have made it to clinical trials.

“Currently, among the known drug targets, only about 20% possess active sites that can be bound by traditional small molecule inhibitors,” Zhang said. “The remaining 80% are considered undruggable or difficult to target with conventional approaches. There is a significant potential that the 80% of undruggable targets could be addressed using PROTAC technology.”