ANN ARBOR, Michigan — Many modern cancer drugs typically target a specific protein or signaling pathway to treat tumors.
Now, researchers at the University of Michigan Health Rogel Cancer Center are taking a new approach by throwing a molecular wrench into the machinery driving prostate cancer. In preclinical studies, this new approach demonstrated greater antitumor activity while sparing normal cells.
The approach targets two proteins that work together to activate genes that fuel prostate cancer growth. Instead of blocking their interaction, researchers glued them together using a specially designed bifunctional small molecule, reprogramming the network of interactions between proteins. The result: greater antitumor activity than a combination of inhibitors targeting the two proteins separately, with less toxicity to normal cells.
"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 senior study author Arul M. Chinnaiyan, MD, PhD, director of the Michigan Center for Translational Pathology and S.P. Hicks Professor of Pathology at Michigan Medicine.
"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," Chinnaiyan said.
The two proteins are the androgen receptor, or AR, and a helper protein called p300. The researchers call the new approach DALTAC, short for domain-alteration chimeras.
The findings are published in Nature .
The work adds to an emerging field known as chemically induced proximity, which uses small molecules to bring proteins together and alter cellular functions. One approach uses proteolysis-targeting chimeras, or PROTACs, to induce the degradation of specific proteins. Another approach is known as transcriptional/epigenetic chemically induced proximity, or TCIP.
"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," said senior study author Shaomeng Wang, PhD, Warner-Lambert/Parke-Davis Professor in Medicine, professor of internal medicine, pharmacology and medicinal chemistry, and director of the Michigan Center for Therapeutic Innovation.
"Our optimized molecule is approximately 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," Wang said.
The work reflects a close collaboration between the Chinnaiyan laboratory, which specializes in prostate cancer biology, and the Wang laboratory, which brings extensive expertise in medicinal chemistry and drug discovery.
The teams evaluated the approach in prostate cancer cell lines, mouse models and three-dimensional organoids derived from human cells. The DALTAC molecules were substantially more potent and effective at killing tumor cells than the combination of AR and p300 inhibitors, while showing strong selectivity for tumor cells over normal cells. In animal models, the approach produced durable responses and was effective against tumors that had become resistant to standard treatments.
"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."
The research is still at the preclinical stage.
"Our teams are working closely to identify a drug candidate suitable for testing in human clinical trials," Wang said.
The researchers believe that reprogramming protein interactions could provide a broadly applicable strategy for drug development, with potential applications in cancers beyond prostate cancer and proteins beyond AR and p300.
The co-first authors of this study are Jie Luo from Chinnaiyan Lab and Jianzhang Yang from Wang Lab. Additional authors are: Jean Ching-Yi Tien, Mi Wang, Sumit Das, Xiaoju Wang, Eleanor Young, Jelena Tosovic, Rahul Mannan, Weiguo Xiang, Xia Jiang, Jocelyn Cai, Yihan Liu, Kenneth Gu, Somnath Mahapatra, Shiting Li, Yitong Yin, Sanjana Eyunni, Abigail J. Todd, Shicheng Jin, Xuhong Cao, Fengyun Su, Stephanie J. Miner, Ranga Sudharshan, Arvind Rao, Abhijit Parolia, Yuanyuan Qiao.
Funding for this work is from Prostate Cancer Foundation, National Cancer Institute grants P50-CA186786, R35-CA231996, R01-CA289013; Department of Defense Prostate Cancer Research Program grant HT9425-26-1-E093; Medsyn Biopharma. Chinnaiyan is a Howard Hughes Medical Institute Investigator, A. Alfred Taubman Scholar and American Cancer Society Professor.
This work was supported by the Rogel Cancer Center Proteomics Resource Facility Shared Resource.
Disclosure: Wang and Chinnaiyan are cofounders of and hold equity in Medsyn Biopharma. The University of Michigan has filed patents related to the AR-p300 DALTACs, which have been licensed to Medsyn. U-M has received a research contract from Medsyn, for which Wang serves as the principal investigator.
Paper cited: "Domain-alteration chimeras rewire oncogenic complexes in prostate cancer," Nature. DOI: 10.1038/s41586-026-11262-4
Resources:
University of Michigan Rogel Cancer Center, www.rogelcancercenter.org
Michigan Medicine Cancer AnswerLine, 800-865-1125
