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. Here, we describe a second-generation AR pan-antagonist (UT-34) that degrades the AR and AR splice variants. 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. Collectively, UT-34 exhibits the properties necessary for a next-generation prostate cancer drug.
Acknowledgement. BGS acknowledges work performed at the Center for Nanophase Materials Sciences, a DOE Office of Science User Facility. VB acknowledges Laboratory Directed Research and Development program of Oak Ridge National Laboratory, managed by UTBattelle, LLC, for the U.S. Department of Energy.
- prostate cancer
- Castration-Resistant Prostate Cancer (CRPC)
- androgen receptor (AR)
- AR degrader (SARD)
- enzalutamide-resistant prostate cancer
- CYP17A1 INHIBITOR
- SPLICE VARIANT
- DIFFERENTIAL REGULATION
- INCREASED SURVIVAL