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

Luo, J.; Yang, J.; Tien, J. C.-Y.; Wang, M.; Das, S.; Xiang, W.; Young, E.; Tosovic, J.; Mannan, R.; Cai, J.; Liu, Y.; Gu, K.; Mahapatra, S.; Li, S.; Yin, Y.; Eyunni, S.; Todd, A. J.; Jin, S.; Cao, X.; Miner, S. J.; Sudharshan, R.; Rao, A.; Parolia, A.; Qiao, Y.; Wang, S.; Chinnaiyan, A. M.

doi:10.64898/2026.04.24.720638

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bioRxiv · 10.64898/2026.04.24.720638

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

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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.

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Luo, J., Yang, J., Tien, J. C.-Y., Wang, M., Das, S., Xiang, W., Young, E., Tosovic, J., Mannan, R., Cai, J., Liu, Y., Gu, K., Mahapatra, S., Li, S., Yin, Y., Eyunni, S., Todd, A. J., Jin, S., Cao, X., Miner, S. J., Sudharshan, R., Rao, A., Parolia, A., Qiao, Y., Wang, S., Chinnaiyan, A. M.. 2026-04-28. Rewiring Oncogenic Transcriptional Complexes with Domain-ALTeration Chimeras (DALTACs) in Prostate Cancer. https://doi.org/10.64898/2026.04.24.720638

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