New therapeutic molecules have demonstrated approximately 1,000 times more potency in tumor cells than standard combinations of inhibitors in preclinical prostate cancer tests, according to Bioengineer.
Researchers at the University of Michigan Health Rogel Cancer Center have developed a strategy using domain-alteration chimeras, or DALTACs, to target prostate cancer by reprogramming the interactions between two cancer-driving proteins.
The technique focuses on the androgen receptor (AR) and a transcriptional coactivator protein called p300, which cooperate to fuel malignancy. By using a custom small molecule to link these proteins into an abnormal configuration, the researchers were able to trap them in an inactive state.
“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 at Michigan Medicine, Tomorrow’s World Today.
Targeting the ERG protein
The research addresses a specific vulnerability in prostate cancer involving the ERG protein, which becomes abnormally active when the TMPRSS2 and ERG genes fuse. This genetic rearrangement occurs in roughly half of prostate cancer cases among patients of European ancestry, promoting tumor growth and migration, SciTechDaily.
For years, ERG was considered “undruggable” because it appeared to lack the molecular pockets required for traditional medication attachment. However, according to SciTechDaily, researchers discovered an accessible pocket in the PNT domain that regulates how ERG interacts with other proteins.
The team screened more than 1,600 compounds to identify a molecule that could bind to this domain, eventually refining it into an experimental compound known as PBITE-1.
“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,” Chinnaiyan said, SciTechDaily.
Selectivity in preclinical models
The investigators tested the bifunctional molecules across several laboratory systems, including cultured prostate cancer cell lines, mouse models, and three-dimensional organoid cultures derived from patient tissues. Bioengineer reports that the DALTACs demonstrated strong selectivity for malignant tissue over healthy cells.
Because healthy cells lack the specific cooperative interactions between AR and p300 that drive tumor progression, the treatment avoided significant toxicity in noncancerous populations, Bioengineer.
“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,” Arul M. Chinnaiyan, MD, PhD, director of the Michigan Center for Translational Pathology and S.P. Hicks Professor of Pathology at Michigan Medicine, said, Tomorrow's World Today.
The molecules also remained effective against tumor lines that had developed resistance to standard oncological regimens, Bioengineer.
Development of oral therapies
The researchers have worked to optimize these molecules for oral bioavailability, a necessary step for developing the treatment into a pill for patients, Bioengineer.
“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 Shaomeng Wang, director of the Michigan Center for Therapeutic Innovation, Tomorrow’s World Today.
While the results in laboratory models are significant, the research remains in the preclinical stage. The research team is currently working to identify a drug candidate suitable for testing in human clinical trials, Tomorrow’s World Today.
Technical methodology and study details
The study, “Domain-alteration chimeras rewire oncogenic complexes in prostate cancer,” was published in Nature on November 11, 2026 (DOI: 10.1038/s41586-026-11262-4). Jie Luo from the Chinnaiyan laboratory and Jianzhang Yang from the Wang laboratory served as co-first authors leading the research. Shaomeng Wang, PhD, serves as the Warner-Lambert/Parke-Davis Professor in Medicine and holds appointments in pharmacology and medicinal chemistry at Michigan Medicine.
To model the ternary AR–JZY3032–p300 complex, investigators used several computational inputs, including AR in complex with JZY3221 and the p300 complex with GNE-049. These were processed through Generate Degrader Complex using 10,000 MCMM steps, a maximum of 5 clashes, and 50 maximum poses. The resulting top 20 predicted complexes underwent refinement using Prime.
The research involved a wide array of cell lines. The American Type Culture Collection (ATCC) provided VCaP, LNCaP, 22Rv1, DU145, PC-3, MCF-7, HepG2, A549, K562, HL-60, U937, HEK293, WPMY-1, U-87 MG, BJAB, SK-ES-1, RD-ES, A204, PBMC, NCI-H526, AU565, MM1.S, SU-DHL-8 and NCI-H211.
REH, TALL-1, NALM6 and MOLT-16 were sourced from the German Collection of Microorganisms and Cell Cultures (DSMZ). The U-87 MG line, which is also listed in the ICLAC Register (ICLAC-00535), was included specifically at the request of a peer reviewer to examine compound activity in an AR+ non-prostate cancer context.
In cell viability assays, VCaP cells were seeded at a density of 10,000 cells per well, while all other prostate cancer cell lines were seeded at 3,000 cells per well.
Funding for this work was provided by various organizations, such as the National Cancer Institute Prostate SPORE Grant (2P50CA186786-11A1), the NCI Early Detection Research Network (U2C-CA271854), the National Natural Science Foundation of China (22521104), and the Strategic Priority Research Program of the Chinese Academy of Sciences (XDB1060000).