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bioRxivCancer BiologyPreprint

Rewiring Oncogenic Transcriptional Complexes with Domain-ALTerAtion Chimeras (DALTACs) in Prostate Cancer

Jie Luo, Jianzhang Yang, Jean Ching-Yi TieniD, Mi Wang, Sumit Das, Xiaoju Wang, Eleanor Young, Jelena TošovićiD, Rahul MannaniD, Weiguo Xiang, Xia JiangiD, Jocelyn Cai, Yihan Liu, Kenneth Gu, Somnath Mahapatra, Shiting LiiD, Yitong YiniD, Sanjana EyunniiD, Abigail J. ToddiD, Shicheng Jin, Xuhong CaoiD, Fengyun SuiD, Stephanie J. MineriD, Ranga Sudharshan, Arvind RaoiD, , Arul M. ChinnaiyaniD

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Abstract

Transcriptional addiction to the androgen receptor (AR) underlies metastatic castration-resistant prostate cancer (mCRPC), where AR maintains oncogenic programs through domain-specific interactions with the acetyltransferases p300/CBP. 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.

In-depth summary

Claude Opus 5.5 · xhigh effort · 8 Nov 2026 · from the full text of version 2 (24 Sept 2026) · CC BY 4.0

A bifunctional AR–p300/CBP molecule, DALTAC-1, forces a non-native contact between AR and p300 domains, silences AR enhancers and regresses AR-driven prostate tumors in mice while sparing AR-negative lines.

The paper says global p300/CBP inhibition may be toxic to normal tissues, and that existing induced-proximity approaches mostly join proteins that do not normally interact. DALTACs instead force a new domain-domain contact between physiological partners inside an existing complex.

Key results

  1. ShownLinking an AR ligand-binding-domain binder to a p300/CBP bromodomain inhibitor gave DALTAC-1 (JZY3032), far more potent than the two parent inhibitors combined, with oral exposure in mice despite a molecular weight of 975.

    IC50 0.26 nM (LNCaP) and 1.0 nM (22Rv1); reported as >1,000 times more potent than the AR inhibitor plus GNE-049 given together. Oral bioavailability 18.5% vs 6.5% for compound 7 in mice. · Development of AR-p300/CBP DALTACs

  2. ShownDALTAC-1 is lineage-selective: potent in AR-positive prostate cancer lines, minimal activity in AR-negative or AR-positive but ARV-766-resistant lines, and its effect persists after a short pulse.

    IC50 profiling across 46 human cell lines against CBPD-409; reduced activity in Kelly, NCI-H211 and U-87 MG; a 4-hour pulse with washout matched continuous exposure, unlike CBPD-409 or the inhibitor combination. · DALTAC-1 selectively inhibits AR+ PCa; DALTAC-1 reprograms AR+ PCa acetylome; Figure legends

  3. ShownDALTAC-1 induces an AR–p300 ternary complex that needs both ligands on one molecule. It links the AR ligand-binding domain to the p300 core region, and a structural model predicts the interface.

    BLI apparent Kd 333.1 nM with 10 μM DALTAC-1 and little to no detectable binding without it; unlinked inhibitors and the Neg-1/Neg-2 controls failed. MM-GBSA −161.8 ± 0.6 kcal/mol (ternary) vs −81.4 (AR) and −90.3 (p300) binary; interface mutants impaired complex formation. · DALTAC-1 induces AR-p300 ternary complex

  4. SuggestedDALTAC-1 removes H2BK20ac and H3K27ac without degrading p300/CBP, and raises AR and cofactor acetylation. On chromatin, AR and p300 increase at palindromic AREs, while at AR/ERG neo-enhancers ERG and BRD4 binding is diminished and RNA polymerase II and histone acetylation are almost completely extinguished.

    Acetyl-lysine MS (n=3) showed acetylation gains on AR, SRC2/3, ARID1A/B not seen with the inhibitor combination. RNA-seq (n=2) showed AR, MYC and mTORC1 gene sets down. ChIP-seq in VCaP cells is mostly n=1. · DALTAC-1 reprograms AR+ PCa acetylome; DALTAC-1 blocks oncogenic transcription; DALTAC-1 reshapes AR–p300 enhanceosome

  5. ShownIn mouse xenografts, DALTAC-1 shrank tumors and was well tolerated. In the MDA-PCa-183 PDX it outperformed enzalutamide and ARV-766, with no recurrence after dosing stopped.

    VCaP-CRPC: regression in 12 of 16 tumors with i.p. dosing; oral dosing beat p300i+ARi. MDA-PCa-183 (n=12 for vehicle, DALTAC-1 and enzalutamide; n=11 for ARV-766; 50 days): complete regression; no recurrence over 16 further days vs regrowth with ARV-766. No significant changes in body weight, liver/kidney function or blood counts. · Potent in vivo efficacy of DALTAC-1 in PCa; Figure legends

Methods, data and reproducibility

Medicinal-chemistry design of heterobifunctional AR-ligand/GNE-049 conjugates, screened by proliferation and ternary-complex assays. Mechanism then probed by BLI, IP-MS, acetyl-lysine and TMT proteomics, RNA-seq, ChIP-seq, MD/MM-GBSA modeling, organoids and xenografts.

  • Human prostate and other cancer cell lines (VCaP, LNCaP, 22Rv1, CWR-R1; 46-line IC50 panel) · human · n = 46 cell lines in the panel; n=3 per dose-response
  • VCaP RNA-seq, ChIP-seq, IP-MS and acetyl-lysine/TMT proteomics · human · n = RNA-seq n=2; proteomics n=3; most ChIP-seq n=1 · GEO GSE310948 and GSE310949
  • GEMM-derived mouse prostate organoids · mouse · n = n=4 per condition
  • PDX-derived human prostate organoids · human · n = n=6 per condition
  • VCaP-CRPC xenograft in castrated SCID mice · mouse · n = n=14 to 16 per group
  • MDA-PCa-183 and MDA-PCa-146-12 PDX models · mouse · n = MDA-PCa-183: n=12 per group (n=11 ARV-766) in the benchmark study
Methods & tools
Schrödinger (Prime MM-GBSA, OPLS4), Kallisto, edgeR, limma-voom, fgsea, MACS2, HOMER, MaxQuant, Proteome Discoverer
Reagents & environment
Versions given for Schrödinger 2025-2, Kallisto v0.46.1, edgeR v3.39.6, limma-voom v3.53.10, fgsea v1.24.0, Trimmomatic v0.39, BWA v0.7.17, MaxQuant v2.3.0.0, Proteome Discoverer v3.0.
Reproducibility gaps
No custom code was used. Compound synthesis is only in the Supplementary Methods. GEO accessions are given without URLs. No compute resources are reported for the 1 μs MD run.
Limitations (4)
  • The atomic structure of the ternary complex is unresolved because of the size, flexibility and disordered regions of full-length AR and p300; the model rests on docking, MD and mutagenesis. · stated by the authors
  • Experiments were neither randomized nor blinded, and no sample-size calculation was used. · stated by the authors
  • Most ChIP-seq heatmaps are n=1 and RNA-seq is n=2, so the chromatin redistribution claims rest on limited replication. · noted in this summary
  • Efficacy is shown only in mouse xenograft and PDX models with small groups in some studies; the pharmacokinetics are mouse-only and no human data are presented. · noted in this summary

Read this if you work on induced-proximity drugs or transcription-factor/coactivator targeting and want a worked example of rewiring a complex rather than degrading it.

Citations
1

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