DC

AR-NTD antagonist

A 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
Small molecule
Indication
Metastatic castration-resistant prostate cancer
Stage
DC
AR-NTD antagonist mechanism concept Two-panel illustrative mechanism schematic. The first panel shows the intrinsically disordered androgen receptor N-terminal domain as a moving ensemble in which a transient site appears. The second panel shows a direct NTD binder engaging that site and biasing the still-disordered ensemble toward a transcriptionally inactive state. The schematic does not imply a resolved structure, covalent binding, degradation, effector recruitment, ligand-binding-domain engagement, or established clinical efficacy. DYNAMIC AR-NTD Find a transient NTD site Site appears across the moving ensemble DIRECT NTD BINDING Bias AR toward an inactive ensemble Transcriptionally inactive ensemble favoured AR-NTD antagonist mechanism concept Two-panel illustrative mechanism schematic. The first panel shows the intrinsically disordered androgen receptor N-terminal domain as a moving ensemble in which a transient site appears. The second panel shows a direct NTD binder engaging that site and biasing the still-disordered ensemble toward a transcriptionally inactive state. The schematic does not imply a resolved structure, covalent binding, degradation, effector recruitment, ligand-binding-domain engagement, or established clinical efficacy. DYNAMIC AR-NTD Find a transient NTD site Site appears across the moving ensemble DIRECT NTD BINDING Bias AR toward an inactive ensemble Transcriptionally inactive ensemble favoured
Illustrative mechanism schematic. Not a docked or experimentally resolved structure.

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 binders that stabilise a conformation which cannot recruit the transcriptional machinery. The result is a fully synthetic small molecule rather than a biologic.

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 at the development candidate stage, where candidate characterisation and development planning precede IND-enabling studies. Collaborations continue to deepen disease biology and MoA understanding.

Collaborations

Peptone’s AR-NTD antagonist 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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