Orally bioavailable androgen receptor degrader, potential next-generation therapeutic for enzalutamide-resistant prostate cancer

Suriyan Ponnusamy, Yali He, Dong Jin Hwang, Thirumagal Thiyagarajan, Rene Houtman, Vera Bocharova, Bobby G. Sumpter, Elias Fernandez, Daniel Johnson, Ziyun Du, Lawrence M. Pfeffer, Robert H. Getzenberg, Iain J. McEwan, Duane D. Miller, Ramesh Narayanan

Research output: Contribution to journalArticlepeer-review

51 Scopus citations

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 languageEnglish
Pages (from-to)6764-6780
Number of pages17
JournalClinical Cancer Research
Volume25
Issue number22
DOIs
StatePublished - 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.

FundersFunder number
GTx, Inc.
UT-Battelle
U.S. Department of Energy
Oak Ridge National Laboratory
Laboratory Directed Research and Development

    Fingerprint

    Dive into the research topics of 'Orally bioavailable androgen receptor degrader, potential next-generation therapeutic for enzalutamide-resistant prostate cancer'. Together they form a unique fingerprint.

    Cite this