{"database":"GEO","file_versions":[{"headers":{"Content-Type":["application/json"]},"body":{"files":{"Txt":["ftp://ftp.ncbi.nlm.nih.gov/geo/series/GSE310nnn/GSE310949/suppl/filelist.txt"],"Raw":["ftp://ftp.ncbi.nlm.nih.gov/geo/series/GSE310nnn/GSE310949/suppl/GSE310949_RAW.tar"],"Other":["ftp://ftp.ncbi.nlm.nih.gov/geo/series/GSE310nnn/GSE310949/"]},"type":"primary"},"statusCode":"OK","statusCodeValue":200}],"scores":null,"additional":{"omics_type":["Genomics"],"species":["Homo sapiens"],"gds_type":["Genome binding/occupancy profiling by high throughput sequencing"],"full_dataset_link":["https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE310949"],"repository":["GEO"],"entry_type":["GSE"],"additional_accession":[]},"is_claimable":false,"name":"Rewiring Oncogenic Transcriptional Complexes with Domain-ALTeration Chimeras (DALTACs) in Prostate Cancer [ChIP-seq]","description":"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 cancer","dates":{"publication":"2026/06/18"},"accession":"GSE310949","cross_references":{"GSM":["GSM9313039","GSM9313017","GSM9313038","GSM9313016","GSM9313019","GSM9313018","GSM9313035","GSM9313034","GSM9313015","GSM9313037","GSM9313036","GSM9313031","GSM9313030","GSM9313033","GSM9313032","GSM9313028","GSM9313027","GSM9313029","GSM9313024","GSM9313023","GSM9313026","GSM9313025","GSM9313042","GSM9313020","GSM9313041","GSM9313022","GSM9313021","GSM9313040"],"GPL":["24676"],"GSE":["310949"],"taxon":["Homo sapiens"],"PMID":["[42094447]"]}}