Development of a high-throughput screening assay for small molecule inhibitors of androgen receptor splice variants

A. E. Monaghan, A. Porter, I. Hunter, A. Morrison, S.P. McElroy, Iain McEwan* (Corresponding Author)

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

2 Citations (Scopus)


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-ligand binding domain (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 paper 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 prostate cancer 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

Bibliographical note

AEM was supported by a BBSRC-CASE studentship together with support from IOmet Pharma, (Nine Edinburgh Bioquarter, Little France Road, Edinburgh EH16 4UX, Scotland, UK), NHS Grampian Endowments and the charity Friends of Anchor. The high-throughput assay and screen was developed with support in kind from the Scottish Life Science Alliance (SULSA) assay development programme. We are also grateful to support from Dr Alan Wise (IOmet Pharma) for advice and critical input.


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


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