Development of a High-Throughput Screening Assay for Small-Molecule Inhibitors of Androgen Receptor Splice Variants

Amy E. Monaghan, Alison Porter, Irene Hunter, Angus Morrison, Stuart P. McElroy, Iain J. McEwan (Lead / Corresponding author)

Research output: Contribution to journalArticlepeer-review

3 Citations (Scopus)
70 Downloads (Pure)


The role of the androgen receptor (AR) in the progression of prostate cancer (PCa) is well established and competitive inhibition of AR ligand binding domain (LBD) has been the mainstay of antiandrogen therapies for advanced and metastatic disease. However, the efficacy of such drugs is often limited by the emergence of resistance, mediated through point mutations and receptor splice variants lacking the AR-LBD. As a result, the prognosis for patients with malignant, castrate-resistant disease remains poor. The amino terminal domain (NTD) of the AR has been shown to be critical for AR function. Its modular activation function (AF-1) is important for both gene regulation and participation in protein-protein interactions. However, due to the intrinsically disordered structure of the domain, its potential as a candidate for therapeutic intervention has been generally overlooked. In this article, we describe the design and development of a functional cell-based assay aimed at identifying small-molecule inhibitors of the AR-NTD. We demonstrate the suitability of the assay for high-throughput screening platforms and validate two initial hits emerging from a small, targeted, library screen in PCa cells.

Original languageEnglish
Pages (from-to)111-124
Number of pages14
JournalASSAY and Drug Development Technologies
Issue number3
Early online date23 Mar 2022
Publication statusPublished - 18 Apr 2022


  • androgen receptor
  • AR-vs
  • castrate-resistant prostate cancer
  • high-throughput screen
  • intrinsically disordered structure
  • prostate cancer

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery


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