Domain-alteration chimeras rewire oncogenic complexes in prostate cancer.

DALTAC-1, an AR–p300/CBP domain-alteration chimera, locks the complex in a non-productive state, producing a “super-inhibitory” suppression of AR-driven transcription and proliferation.

• Why it matters: Metastatic castration-resistant prostate cancer depends on androgen receptor domain-specific interactions with p300/CBP, leaving a therapeutic gap for disrupting these native oncogenic complexes.
• What they did: The study engineered DALTAC-1 to enforce non-native domain-domain proximity between AR’s ligand-binding domain and the p300/CBP bromodomain, then profiled transcription, chromatin marks, and complex recruitment.
• The result: DALTAC-1 abolishes H2B N-terminal acetylation, induces neomorphic acetylation of AR and coactivators, collapses the AR neo-enhanceosome, and in multiple in vivo models drives deep, durable tumor regressions with lineage selectivity for AR-p300/CBP dual-dependent cells.

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