Researchers at UNC Lineberger Comprehensive Cancer Center and UNC Eshelman School of Pharmacy have developed a promising new compound that selectively and effectively breaks down a protein linked to various cancers, including multiple myeloma and prostate cancer.
Lindsey James, PhD, and colleagues demonstrated that UNC8732 binds to NSD2, a protein crucial for cancer cell growth and survival. UNC8732 simultaneously recruits another protein, FBXO22, to NSD2 to initiate the degradation process. Using acute lymphoblastic leukemia cell lines, they showed that UNC8732 not only degrades NSD2 but also suppresses cancer cell growth, induces cell death and reverses drug resistance.
The findings, published in Nature Chemical Biology, highlight the potential of UNC8732.
James, a UNC Lineberger member and assistant professor in the Division of Chemical Biology and Medicinal Chemistry at UNC Eshelman, is the study’s co-corresponding author with Cheryl Arrowsmith, PhD, at the University of Toronto. John R. Tabor, PhD, formerly a postdoctoral research associate in the James lab, and David Y. Nie, a graduate student at the Princess Margaret Cancer Centre in Toronto, are the first authors.
Protein degradation is a natural cellular process where damaged or unnecessary proteins are broken down while healthy proteins are spared. This process recycles useful protein elements and destroys those that are no longer beneficial. Targeted protein degradation uses laboratory-made compounds to hijack this process and redirect it against disease-associated proteins.
“This pharmacological approach has enabled the degradation of a wide range of cancer targets, including many previously considered ‘undruggable’ by traditional strategies,” James said. “Targeted degraders also have the potential to be more effective and selective, resulting in distinct pharmacology compared to traditional inhibitors.”
Despite significant interest in targeted protein degradation technologies during the past 20 years, several obstacles have hindered the field’s growth.
“One significant limitation has been the limited number of E3 ligases that we know how to rationally hijack to promote target degradation,” James said. “Currently, only two—VHL [Von Hippel-Lindau] and CRBN [cereblon] — are routinely used. We have highlighted FBXO22 as another candidate E3 ligase for targeted protein degradation, potentially expanding the degradable proteome.”
Additionally, many targeted protein degradation compounds are larger than traditional small-molecule drugs. This often results in poor cell permeability and pharmacological properties, potentially limiting their clinical use.
James and her colleagues are now applying their newly discovered approach to degrade additional therapeutically relevant proteins. Their goal is to demonstrate the broad applicability of FBXO22 recruitment for protein degradation and identify novel lead compounds for further development.
“This discovery of UNC8732 has helped to both improve our understanding of NSD2 biology and generate a lot of excitement around NSD2 as a therapeutic target,” James said.
Authors and disclosures
A complete listing of authors, funding sources and disclosures is available in the published paper.