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Here, we describe a distinct therapeutic modality, Domain-ALTerAtion Chimeras (DALTACs), that rewire endogenous protein complexes by enforcing non-native domain\u2013domain interactions. Our first-in-class AR\u2013p300\/CBP DALTAC-1 induces synthetic proximity between the AR ligand-binding domain and p300\/CBP-bromodomain, misconfiguring their native interface and locking the complex in a non-productive state. DALTAC-1 triggers a \u201csuper-inhibitory\u201d 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 (H2BNTac) while inducing neomorphic acetylation of AR and coactivators, ultimately collapsing the AR neo-enhanceosome. Chromatin profiling revealed redistribution of AR and p300\/CBP toward palindromic AREs, accompanied by disruption of cofactor and transcriptional machinery recruitment at oncogenic AR\/ERG neo-enhancers. DALTAC-1 exhibits exquisite lineage selectivity, displaying potent activity in AR-p300\/CBP dual-dependent cells while sparing AR-negative cells. In multiple in vivo models, DALTAC-1 induces deep and durable tumor regressions. Together, these findings establish DALTACs as a broadly applicable strategy to rewire disease-defining complexes through domain-topology alteration, expanding induced-proximity therapeutics, while DALTAC-1\u2019s precise lineage-selectivity supports its translational potential in AR-driven prostate cancer.\n                <\/jats:p>","DOI":"10.64898\/2026.04.24.720638","type":"posted-content","created":{"date-parts":[[2026,4,29]],"date-time":"2026-04-29T01:25:23Z","timestamp":1777425923000},"source":"Crossref","is-referenced-by-count":2,"title":["Rewiring Oncogenic Transcriptional Complexes with Domain-ALTerAtion Chimeras (DALTACs) in Prostate Cancer"],"prefix":"10.64898","author":[{"given":"Jie","family":"Luo","sequence":"first","affiliation":[{"name":"Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI, USA"},{"name":"Department of Pathology, University of Michigan, Ann Arbor, MI, 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