AR-NTD AvTAC

A bifunctional small molecule that engages the intrinsically disordered N-terminal domain of the androgen receptor to shut down transcriptional signalling that current therapies leave intact.

Target: AR-NTD
Modality: Bifunctional small molecule
Indication: Metastatic castration-resistant prostate cancer
Stage: DC

Target

The androgen receptor N-terminal domain (AR-NTD) carries the receptor's main transcriptional activation function and stays intrinsically disordered in isolation. Because approved antiandrogens bind the ligand-binding domain, splice variants and ligand-independent signalling through the NTD remain a driver of resistance in castration-resistant disease.

Approach

Peptone maps the transient pockets that appear across the AR-NTD ensemble using HDX-MS and GPU-accelerated modelling, then designs bifunctional binders that stabilise a conformation which cannot recruit the transcriptional machinery.

Preclinical

Preclinical work shows target-dependent suppression of AR-driven transcription in cell lines that no longer respond to ligand-binding-domain inhibitors, with activity retained against common AR splice variants. Mechanism-of-action studies are advanced with academic partners at IOR and The Royal Marsden.

Development Plan

The program is advancing toward development-candidate selection, where potency, selectivity, and drug-like properties are being locked down ahead of IND-enabling studies.

Collaborations

Peptone’s AR-NTD AvTAC program is advanced with academic collaborations at the Institute of Oncology Research (Andrea Alimonti) and The Royal Marsden / ICR (Johann de Bono). See Partnering and Collaborations on the pipeline page for detail.

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