Native domain-interaction rewiring collapses the AR neo-enhanceosome in prostate cancer

The androgen receptor (AR) signaling axis remains active in metastatic castration-resistant prostate cancer (mCRPC) through adaptive mechanisms that sustain oncogenic transcriptional programs despite androgen deprivation. AR cooperates with the histone acetyltransferase p300 and other cofactors to assemble cancer-specific “neo-enhanceosomes” via highly organized domain-domain interactions that drive oncogenic gene expression. Here, we introduce a new class of chemical-induced proximity compounds, termed Domain-ALTeration Chimeras (DALTACs), which represent a distinct modality designed to rewire endogenous protein complexes by altering native domain interactions rather than degrading or inhibiting individual proteins. Our first-in-class compound, AR-p300 DALTAC-1, enforces proximity between the AR ligand-binding domain and the p300 bromodomain, thereby miswiring their native architecture and locking the complex in a non-productive configuration. This domain reconfiguration elicits a “super-inhibitory” effect that suppresses AR target gene transcription and cell proliferation more potently than concurrent inhibition of AR and p300. Mechanistically, DALTAC-1 reprograms the substrate spectrum of p300, diminishing histone H2B N-terminal acetylation (H2BNTac) and triggering the collapse of the oncogenic enhancer network. Strikingly, DALTAC-1 displays remarkable lineage selectivity, exerting potent activity in AR-driven prostate cancer cells and organoids while sparing AR-negative or non-prostate lineage tissues. In multiple prostate cancer models, DALTAC-1 exhibits robust antitumor efficacy and tumor regression with favorable tolerability. Collectively, this study establishes the DALTAC modality as a new therapeutic concept that manipulates protein complex topology to reprogram cellular function, offering a versatile and generalizable strategy to rewire diverse transcriptional, epigenetic, and signaling complexes across different cancer types. Importantly, the exquisite lineage selectivity of DALTAC-1 minimizes effects on normal tissues, underscoring its strong clinical translational potential with a low likelihood of safety concerns.