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

  • Clin Cancer Res. 2019 Nov 15;25(22):6764-6780. doi: 10.1158/1078-0432.CCR-19-1458.
Suriyan Ponnusamy  1 ,  Yali He  2 ,  Dong-Jin Hwang  2 ,  Thirumagal Thiyagarajan  1 ,  Rene Houtman  3 ,  Vera Bocharova  4 ,  Bobby G Sumpter  4 ,  Elias Fernandez  5 ,  Daniel Johnson  6 ,  Ziyun Du  7 ,  Lawrence M Pfeffer  7 ,  Robert H Getzenberg  8 ,  Iain J McEwan  9 ,  Duane D Miller  2 ,  Ramesh Narayanan  10  11
Affiliations
  • 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. [email protected].
  • 11. West Cancer Center, Memphis, Tennessee.
PMID: 31481513 DOI: 10.1158/1078-0432.CCR-19-1458
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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