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.
Original language | English |
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Pages (from-to) | 6764-6780 |
Number of pages | 17 |
Journal | Clinical Cancer Research |
Volume | 25 |
Issue number | 22 |
DOIs | |
State | Published - Nov 15 2019 |
Funding
B.G. Sumpter acknowledges work performed at the Center for Nanophase Materials Sciences, a DOE Office of Science User Facility. V. Bocharova acknowledges Laboratory Directed Research and Development program of Oak Ridge National Laboratory, managed by UT-Battelle, LLC, for the U.S. Department of Energy. The work in this manuscript was funded by GTx, Inc.
Funders | Funder number |
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GTx, Inc. | |
UT-Battelle | |
U.S. Department of Energy | |
Oak Ridge National Laboratory | |
Laboratory Directed Research and Development |