Evidence map›Paper›PMID 42094447›Full record

ArticlebioRxiv : the preprint server for biology2026

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

Jie Luo, Jianzhang Yang, Jean Ching-Yi Tien, Mi Wang, Sumit Das, Weiguo Xiang, Eleanor Young, Jelena Tosovic, Rahul Mannan, Jocelyn Cai and 16 more

Abstract readPreprint
PubMed Full text at PMC Publisher
In one paragraph

Article in bioRxiv : the preprint server for biology, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.

0numbers the graph read from it
0cells of the map it votes in
0citing papers in PubMed
–field-weighted citation impact
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

0 citing papers in PubMed.

No citing paper in PubMed yet.

4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

26 authors.

Jie LuoMichigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI, USA.
Jianzhang YangDivision of Hematology-Oncology, Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA.
Jean Ching-Yi TienMichigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI, USA.
Mi WangDivision of Hematology-Oncology, Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA.
Sumit DasMichigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI, USA.
Weiguo XiangDivision of Hematology-Oncology, Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA.
Eleanor YoungMichigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI, USA.
Jelena TosovicDivision of Hematology-Oncology, Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA.
Rahul MannanMichigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI, USA.
Jocelyn CaiMichigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI, USA.
Yihan LiuMichigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI, USA.
Kenneth GuMichigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI, USA.
Somnath MahapatraMichigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI, USA.
Shiting LiMichigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI, USA.
Yitong YinMichigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI, USA.
Sanjana EyunniMichigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI, USA.
Abigail J ToddMichigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI, USA.
Shicheng JinDivision of Hematology-Oncology, Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA.
Xuhong CaoMichigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI, USA.
Stephanie J MinerMichigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI, USA.
Ranga SudharshanDepartment of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, MI, USA.
Arvind RaoDepartment of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, MI, USA.
Abhijit ParoliaMichigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI, USA.
Yuanyuan QiaoMichigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI, USA.
Shaomeng WangMichigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI, USA.
Arul M ChinnaiyanMichigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI, USA.ORCID 0000-0001-9282-3415

Funding

Tissue/InformaticsP50CA186786 · NCI · UNIVERSITY OF MICHIGAN AT ANN ARBOR · PI Ganesh S Palapattu · 2014 to 2026
$27.6M
Exploring Precision Oncology: From Gene Fusions to lncRNAsR35CA231996 · NCI · UNIVERSITY OF MICHIGAN AT ANN ARBOR · PI CHINNAIYAN, ARUL M · 2018 to 2024
$6.4M
Orally active CBP/p300 degradersR01CA289013 · NCI · UNIVERSITY OF MICHIGAN AT ANN ARBOR · PI SHAOMENG WANG · 2024 to 2026
$2.0M
NCI NIH HHS P50 CA186786NCI NIH HHS R01 CA289013NCI NIH HHS R35 CA231996
6 · The paper itself

Abstract

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 acetyltransferases p300/CBP 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/CBP DALTAC-1, induces a synthetic proximity between the AR ligand-binding domain and the p300/CBP bromodomain, thereby misconfiguring the native AR-p300/CBP 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/CBP inhibition. Mechanistically, DALTAC-1 reprograms the substrate specificity of p300/CBP, 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 broadly 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.

Indexed as

androgen receptorchemical-induced proximityDALTACneo-enhanceosomep300/CBPprostate cancer

Identifiers

PMID42094447
PMCPMC13142405

What OpenQuestion holds

Textmetadata
LicenceCC BY
Read underepoch 390

Registered trials

None linked

Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.