Rewiring oncogenic transcriptional complexes with domain-alteration chimeras (DALTACs) in prostate cancer

ABSTRACT: Transcriptional addiction to the androgen receptor (AR) underlies metastatic castration-resistant prostate cancer (mCRPC)1, where AR maintains oncogenic programs through domain-specific interactions with the acetyltransferases p300/CBP2. Here, we describe a distinct 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 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 “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 (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’s precise lineage-selectivity supports its translational potential in AR-driven prostate cancer.

INSTRUMENT(S):

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Permanent Cell Line Cell, Cell Culture

DISEASE(S): Prostate Adenocarcinoma

SUBMITTER: Jie Luo  

LAB HEAD: Arul Chinnaiyan

PROVIDER: PXD084250 | Pride | 2026-10-30

REPOSITORIES: Pride