Domain-alteration chimeras rewire oncogenic complexes in prostate cancer

Abstract Transcriptional addiction to the androgen receptor (AR) underlies metastatic castration-resistant prostate cancer 1 , in which AR maintains oncogenic programs through domain-specific interactions with the acetyltransferases p300 and CBP (collectively p300/CBP) 2 . Here we describe a novel therapeutic modality, domain-alteration chimeras (DALTACs), that rewire endogenous protein complexes by enforcing non-native domain–domain interactions. Our first-in-class AR–p300/CBP DALTAC-1 induces synthetic proximity between the ligand-binding domain of AR and the bromodomain of p300/CBP, misconfiguring their native interface and locking the complex in a non-productive state. DALTAC-1 triggers a ‘super-inhibitory’ effect, suppressing AR-driven transcription and proliferation more potently than combined AR and p300/CBP inhibition. Mechanistically, DALTAC-1 reprograms p300/CBP substrate engagement, abolishing the histone mark H2B N-terminal acetylation and inducing neomorphic acetylation of AR and coactivators, ultimately collapsing the AR neo-enhanceosome. Chromatin profiling revealed redistribution of AR and p300/CBP towards palindromic androgen response elements, accompanied by disruption of cofactor and transcriptional machinery recruitment at oncogenic AR and ERG neo-enhancers. DALTAC-1 exhibits exquisite lineage selectivity, displaying potent activity in AR–p300/CBP dual-dependent cells and sparing AR-negative cells. In multiple in vivo models, DALTAC-1 induces deep and durable tumour regressions. Together, these findings establish DALTACs as a broadly applicable strategy to rewire disease-defining complexes through domain-topology alteration, expanding induced-proximity therapies, and the precise lineage selectivity of DALTAC-1 supports its translational potential in AR-driven prostate cancer.