Open AccessDevelopment of a High-Throughput Screening Assay for Small-Molecule Inhibitors of Androgen Receptor Splice Variants
Author(s) -
Amy E. Monaghan,
Alison Porter,
Irene Hunter,
Angus J. Morrison,
Stuart P. McElroy,
Iain J. McEwan
Publication year - 2022
Publication title -
assay and drug development technologies
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.402
H-Index - 56
eISSN - 1557-8127
pISSN - 1540-658X
DOI - 10.1089/adt.2021.128
Subject(s) - androgen receptor , small molecule , prostate cancer , computational biology , cancer research , high throughput screening , biology , drug discovery , flutamide , androgen receptor antagonists , bioinformatics , cancer , genetics
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.