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

  • bioRxiv. 2026 Apr 28:2026.04.24.720638. doi: 10.64898/2026.04.24.720638.
Jie Luo  1  2  3 ,  Jianzhang Yang  4  3 ,  Jean Ching-Yi Tien  1  2  5 ,  Mi Wang  4 ,  Sumit Das  1  2 ,  Weiguo Xiang  4 ,  Eleanor Young  1 ,  Jelena Tosovic  4 ,  Rahul Mannan  1  2 ,  Jocelyn Cai  1 ,  Yihan Liu  1  6 ,  Kenneth Gu  1 ,  Somnath Mahapatra  1  2 ,  Shiting Li  1 ,  Yitong Yin  1 ,  Sanjana Eyunni  1  2 ,  Abigail J Todd  1 ,  Shicheng Jin  4 ,  Xuhong Cao  1  2  7 ,  Stephanie J Miner  1  2 ,  Ranga Sudharshan  8 ,  Arvind Rao  8 ,  Abhijit Parolia  1  2  5  9 ,  Yuanyuan Qiao  1  2  5 ,  Shaomeng Wang  1  4  5  10  11 ,  Arul M Chinnaiyan  1  2  5  7  9
Affiliations
  • 1. Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI, USA.
  • 2. Department of Pathology, University of Michigan, Ann Arbor, MI, USA.
  • 3. These authors contributed equally.
  • 4. Division of Hematology-Oncology, Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA.
  • 5. Rogel Cancer Center, University of Michigan, Ann Arbor, MI, USA.
  • 6. Cancer Biology Program, University of Michigan, Ann Arbor, MI, USA.
  • 7. Howard Hughes Medical Institute, University of Michigan, Ann Arbor, MI, USA.
  • 8. Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, MI, USA.
  • 9. Department of Urology, University of Michigan, Ann Arbor, MI, USA.
  • 10. Department of Pharmacology, University of Michigan, Ann Arbor, MI, USA.
  • 11. Department of Medicinal Chemistry, University of Michigan, Ann Arbor, MI, USA.
PMID: 42094447 DOI: 10.64898/2026.04.24.720638
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.

Keywords
DALTAC; androgen receptor; chemical-induced proximity; neo-enhanceosome; p300/CBP; prostate cancer.
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