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

Area of Science:

• Oncology
• Molecular Biology
• Drug Discovery

Background:

• Metastatic castration-resistant prostate cancer (mCRPC) is driven by transcriptional addiction to the androgen receptor (AR).
• AR maintains oncogenic enhancer programs via interactions with p300/CBP and cofactors.
• Current therapies often target individual components, leading to resistance.

Purpose of the Study:

• To introduce Domain-ALTeration Chimeras (DALTACs) as a novel therapeutic modality for mCRPC.
• To investigate the mechanism of action of the first-in-class molecule, AR-p300/CBP DALTAC-1.
• To evaluate the efficacy and selectivity of DALTAC-1 in preclinical models.

Main Methods:

• Design and synthesis of AR-p300/CBP DALTAC-1 to induce synthetic proximity between AR and p300/CBP.
• Assessment of transcriptional activity, proliferation, and protein acetylation.
• Chromatin profiling (ChIP-seq) to analyze AR, p300, ERG, BRD4, and RNA polymerase II binding.
• In vitro studies using prostate cancer cell lines and patient-derived organoids.
• In vivo studies using castration-resistant and patient-derived xenograft models.

Main Results:

• DALTAC-1 induced a transcriptionally inert AR-p300/CBP complex, causing potent suppression of AR-driven transcription and proliferation.
• DALTAC-1 reprogrammed p300/CBP substrate specificity, leading to collapse of the AR neo-enhanceosome.
• Chromatin profiling showed redistribution of AR and p300, attenuation of ERG/BRD4 recruitment, and loss of key histone marks at oncogenic enhancers.
• DALTAC-1 demonstrated exquisite lineage selectivity for AR-positive prostate cancer cells and organoids.
• In vivo models showed deep and durable tumor regressions with favorable tolerability.

Conclusions:

• DALTACs represent a broadly applicable strategy to rewire disease-defining protein complexes by altering domain topology.
• AR-p300/CBP DALTAC-1 is a first-in-class agent with strong translational potential for treating AR-driven prostate cancer.
• This approach expands the therapeutic landscape of induced proximity agents.