Domain-alteration chimeras rewire oncogenic complexes in prostate cancer

Scientists at the University of Michigan Health Rogel Cancer Center have created a new class of therapeutic molecules called domain-alteration chimeras, or DALTACs, that rewire oncogenic protein complexes in prostate cancer. The lead compound, DALTAC-1 (JZY3032), connects the ligand-binding domain of the androgen receptor (AR) to the bromodomain of the acetyltransferases p300 and CBP, forcing a non-native interaction that locks the complex in an inactive state. This "molecular brace" approach shuts down two oncogenic signaling pathways simultaneously, producing what the researchers describe as a "super-inhibitory" effect that is more potent than combining separate AR and p300/CBP inhibitors.

The work, published in Nature, emerges from a collaboration between the laboratory of Arul M. Chinnaiyan, MD, PhD, director of the Michigan Center for Translational Pathology, and the drug discovery team led by Shaomeng Wang, PhD, director of the Michigan Center for Therapeutic Innovation. Chinnaiyan said, "Our molecule acts like a molecular brace, connecting these two cancer-driving proteins in an abnormal configuration that traps them in an inactive state. This shuts down two oncogenic signaling pathways simultaneously, enabling highly effective killing of tumor cells while sparing normal cells." Wang added, "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."

DALTAC-1 achieved half-maximal inhibitory concentrations of 0.26 nM in LNCaP cells and 1.0 nM in 22Rv1 cells, outperforming enzalutamide, darolutamide, the AR PROTAC degrader ARV-766, and the AR–BRD4 RIPTAC-1. In mouse models, the compound showed 18.5% oral bioavailability despite a molecular mass of 975 Da and induced deep, durable tumor regressions without overt toxicity. The molecule also retained activity in models resistant to standard treatments, including those expressing the AR-V7 splice variant. A four-hour pulse of DALTAC-1 followed by washout produced inhibition comparable to continuous exposure, whereas the p300/CBP dual degrader CBPD-409 and the inhibitor combination lost activity after washout.

Mechanistically, DALTAC-1 reprograms p300/CBP substrate engagement, abolishing the histone mark H2B N-terminal acetylation and inducing neomorphic acetylation of AR and coactivators, which collapses the AR neo-enhanceosome. Chromatin profiling revealed redistribution of AR and p300/CBP toward palindromic androgen response elements and disruption of cofactor recruitment at oncogenic enhancers. The compound displayed exquisite lineage selectivity, potently inhibiting AR-positive, p300/CBP-dependent prostate cancer cells while sparing AR-negative cells. The researchers are now working to identify a drug candidate suitable for human clinical trials and believe the domain-rewiring strategy could apply broadly to other cancers and protein complexes.