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

Abstract

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
Number of pages14
JournalASSAY and Drug Development Technologies
Early online date23 Mar 2022
DOIs
Publication statusE-pub ahead of print - 23 Mar 2022

Keywords

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

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