University of Michigan Health Rogel Cancer Center researchers found a pocket in the PNT domain of the cancer-driving protein ERG, targeting prostate cancer cases driven by the TMPRSS2-ERG gene fusion.
This genetic rearrangement occurs in prostate cancer cases, promoting tumor cell growth. ERG lacked the pockets where medications attach, so researchers considered it undruggable for years.
The team identified a way to target the protein by conceptualizing the compound PBITE-1. Tests on human and mouse prostate tissue models and prostate cancer cell lines showed that this compound suppressed ERG function, induced cancer cell death, and decreased the cancer cells’ capacity to invade neighboring tissue.
“Although we were the first to identify the gene fusion as a driver of prostate cancer, it was challenging to find a drug target for ERG,” said Arul Chinnaiyan, M.D., Ph.D., S.P. Hicks Professor of Pathology.
Most existing therapies focus on androgen receptors that respond to testosterone. Drugs that block androgen signaling slow the disease, but tumors develop resistance and treatments cause side effects.
“Although it is unlikely that PBITE-1 is ready to become a drug any time soon, this study shows that ERG is a druggable target,” Chinnaiyan said. “It is exciting that we now have a path forward to target ERG in prostate cancer.”
The Proceedings of the National Academy of Sciences released these results on 7 July 2026, featuring the headline “A ligandable PNT domain establishes ERG as a directly targetable oncogenic driver in prostate cancer.” The study included contributions from co-authors Xiaoju Wang, Wenyan Liu, Jiehao Yang, Jean Ching-Yi Tien, Yu Chang, Rahul Mannan, Somnath Mahapatra, Yang Zhou, Lihao Gan, Xuhong Cao, Jiayi Zhou, Yuping Zhang, Sharpkate Shaker, Yichao Huang, Hang Qiao, Rudana Hamadeh, Grafton Ervine, Cynthia Wang, Fengyun Su, Rui Wang, Lanbo Xiao, Raghunath Ranga Sudharshan, Arvind Rao, Zaneta Nikolovska-Coleska, Cole Stephens, Lifeng Liu, Debashish Sahu, Jeanne Stuckey, Zhen Wang, Ke Ding, and Arul M. Chinnaiyan.
Investigators at the Rogel Cancer Center introduced a preclinical therapeutic strategy called domain-alteration chimeras, or DALTACs, in a separate study published on November 11, 2026, in Nature, targeting the androgen receptor and a transcriptional coactivator protein called p300.
“Our molecule acts like a molecular brace, connecting these two cancer-driving proteins in an abnormal configuration that traps them in an inactive state,” said Arul M. Chinnaiyan, director of the Michigan Center for Translational Pathology and S.P. Hicks Professor of Pathology.
“This shuts down two oncogenic signaling pathways simultaneously, enabling highly effective killing of tumor cells while sparing normal cells. Our preclinical findings suggest that this approach could offer a more effective treatment strategy for prostate cancer.”
Collaboration brought together Chinnaiyan’s biology laboratory and a medicinal chemistry group headed by Shaomeng Wang, Ph.D., who leads the Michigan Center for Therapeutic Innovation and holds roles as professor of internal medicine, pharmacology, and medicinal chemistry, alongside the Warner-Lambert/Parke-Davis Professorship in Medicine at Michigan Medicine. Jie Luo from Chinnaiyan’s team and Jianzhang Yang from Wang’s team served as the co-first authors who jointly directed the published research.
“Our molecules consist of two inhibitors joined by a carefully designed short linker. By gluing two cancer-driving proteins together, they alter the proteins’ natural interactions,” Wang said.
“Our optimized molecule is about 1,000 times more potent in tumor cells than the combination of inhibitors targeting these proteins separately, while sparing normal cells that lack these interactions. We also optimized the molecules for oral bioavailability, a key step toward developing a pill for patients.”
The research team evaluated the strategy across cultured prostate cancer cell lines, experimental mouse models, and three-dimensional organoid cultures derived from patient tissues. Tests demonstrated selectivity for malignant tissue and durable therapeutic responses in animal models, including tumor lines that resisted standard regimens.
“These are remarkable preclinical results,” Chinnaiyan said. “The durable responses suggest an opportunity to develop a more effective treatment for advanced prostate cancer, including castration-resistant prostate cancer, if these findings translate to patients.”
“Our teams are working closely to identify a drug candidate suitable for testing in human clinical trials,” Wang said.