GEOapplication/xmlftp://ftp.ncbi.nlm.nih.gov/geo/series/GSE310nnn/GSE310949/suppl/filelist.txtftp://ftp.ncbi.nlm.nih.gov/geo/series/GSE310nnn/GSE310949/suppl/GSE310949_RAW.tarftp://ftp.ncbi.nlm.nih.gov/geo/series/GSE310nnn/GSE310949/primaryOK200GenomicsHomo sapiensGenome binding/occupancy profiling by high throughput sequencinghttps://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE310949GEOGSEfalseRewiring Oncogenic Transcriptional Complexes with Domain-ALTeration Chimeras (DALTACs) in Prostate Cancer [ChIP-seq]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 acetyltransferase p300 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 DALTAC-1, induces a synthetic proximity between the AR ligand-binding domain and the p300 bromodomain, thereby misconfiguring the native AR–p300 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 inhibition. Mechanistically, DALTAC-1 reprograms the substrate specificity of p300, 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 universally 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 cancer2026/06/18GSE310949GSM9313039GSM9313017GSM9313038GSM9313016GSM9313019GSM9313018GSM9313035GSM9313034GSM9313015GSM9313037GSM9313036GSM9313031GSM9313030GSM9313033GSM9313032GSM9313028GSM9313027GSM9313029GSM9313024GSM9313023GSM9313026GSM9313025GSM9313042GSM9313020GSM9313041GSM9313022GSM9313021GSM931304024676310949Homo sapiens[42094447]