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Clin Cancer Res. 2019 Nov 15;25(22):6764-6780. doi: 10.1158/1078-0432.CCR-19-1458. Epub 2019 Sep 3.

Orally Bioavailable Androgen Receptor Degrader, Potential Next-Generation Therapeutic for Enzalutamide-Resistant Prostate Cancer.

Author information

1
Department of Medicine, University of Tennessee Health Science Center, Memphis, Tennessee.
2
Department of Pharmaceutical Sciences, University of Tennessee Health Science Center, Memphis, Tennessee.
3
PamGene International, Den Bosch, the Netherlands.
4
Oak Ridge National Laboratory, Oak Ridge, Tennessee.
5
Biochemistry and Cell & Molecular Biology, University of Tennessee, Knoxville, Tennessee.
6
Molecular Bioinformatics Core, University of Tennessee Health Science Center, Memphis, Tennessee.
7
Department of Pathology, University of Tennessee Health Science Center, Memphis, Tennessee.
8
GTx, Inc., Memphis, Tennessee.
9
Institute of Medical Sciences, School of Medicine, Medical Sciences and Nutrition, University of Aberdeen, Aberdeen, Scotland, United Kingdom.
10
Department of Medicine, University of Tennessee Health Science Center, Memphis, Tennessee. rnaraya4@uthsc.edu.
11
West Cancer Center, Memphis, Tennessee.

Abstract

PURPOSE:

Androgen receptor (AR)-targeting prostate cancer drugs, which are predominantly competitive ligand-binding domain (LBD)-binding antagonists, are inactivated by common resistance mechanisms. It is important to develop next-generation mechanistically distinct drugs to treat castration- and drug-resistant prostate cancers.

EXPERIMENTAL DESIGN:

Second-generation AR pan antagonist UT-34 was selected from a library of compounds and tested in competitive AR binding and transactivation assays. UT-34 was tested using biophysical methods for binding to the AR activation function-1 (AF-1) domain. Western blot, gene expression, and proliferation assays were performed in various AR-positive enzalutamide-sensitive and -resistant prostate cancer cell lines. Pharmacokinetic and xenograft studies were performed in immunocompromised rats and mice.

RESULTS:

UT-34 inhibits the wild-type and LBD-mutant ARs comparably and inhibits the in vitro proliferation and in vivo growth of enzalutamide-sensitive and -resistant prostate cancer xenografts. In preclinical models, UT-34 induced the regression of enzalutamide-resistant tumors at doses when the AR is degraded; but, at lower doses, when the AR is just antagonized, it inhibits, without shrinking, the tumors. This indicates that degradation might be a prerequisite for tumor regression. Mechanistically, UT-34 promotes a conformation that is distinct from the LBD-binding competitive antagonist enzalutamide and degrades the AR through the ubiquitin proteasome mechanism. UT-34 has a broad safety margin and exhibits no cross-reactivity with G-protein-coupled receptor kinase and nuclear receptor family members.

CONCLUSIONS:

Collectively, UT-34 exhibits the properties necessary for a next-generation prostate cancer drug.

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