Rewiring Oncogenic Transcriptional Complexes with Domain-ALTeration Chimeras (DALTACs) in Prostate Cancer.

Transcriptional addiction to the androgen receptor (AR) underlies metastatic castration-resistant prostate cancer (mCRPC), where AR maintains oncogenic enhancer programs through dynamic, domain-specific interactions with the lysine acetyltransferases p300/CBP and associated cofactors. Here, we describe a mechanistically distinct therapeutic modality, Domain-ALTeration Chimeras (DALTACs), designed to rewire endogenous protein complexes by enforcing non-native domain-domain interactions rather than degrading or inhibiting individual components. Our first-in-class molecule, AR-p300/CBP DALTAC-1, induces a synthetic proximity between the AR ligand-binding domain and the p300/CBP bromodomain, thereby misconfiguring the native AR-p300/CBP interface and locking the complex into a non-productive, transcriptionally inert state. DALTAC-1 triggers a profound "super-inhibitory" effect, suppressing AR-driven transcription and proliferation more potently than combined AR and p300/CBP inhibition. Mechanistically, DALTAC-1 reprograms the substrate specificity of p300/CBP, extinguishing the enhancer-associated histone mark H2B N-terminal acetylation (H2BNTac) while inducing neomorphic acetylation of AR and SRC2/3, culminating in collapse of the AR neo-enhanceosome. Chromatin profiling revealed widespread redistribution of AR and p300 toward canonical palindromic AREs, coupled with attenuation of ERG/BRD4 recruitment and a near complete loss of histone H2BNTac acetylation and RNA polymerase II loading at oncogenic AR/ERG neo-enhancers. Strikingly, DALTAC-1 exhibits exquisite lineage selectivity, displaying potent activity in AR-positive prostate cancer cells and patient-derived organoids while sparing AR-negative or non-prostate lineages. In multiple in vivo models, including castration-resistant and patient-derived xenograft tumors, DALTAC-1 induces deep and durable tumor regressions with favorable tolerability. Together, these findings establish DALTACs as a broadly applicable strategy to rewire disease-defining protein complexes by altering their domain topology, expanding the conceptual and therapeutic landscape of induced proximity agents. The precision and lineage-selective action of DALTAC-1 highlight its strong translational potential for treating AR-driven prostate cancer.