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

• Published in: Clinical cancer research Vol. 25; no. 22; pp. 6764 - 6780
• Main Authors: Ponnusamy, Suriyan, He, Yali, Hwang, Dong-Jin, Thiyagarajan, Thirumagal, Houtman, Rene, Bocharova, Vera, Sumpter, Bobby G, Fernandez, Elias, Johnson, Daniel, Du, Ziyun, Pfeffer, Lawrence M, Getzenberg, Robert H, McEwan, Iain J, Miller, Duane D, Narayanan, Ramesh
• Format: Journal Article
• Language: English
• Published: United States American Association for Cancer Research 15.11.2019
• Subjects: 60 APPLIED LIFE SCIENCES; Administration, Oral; androgen receptor (AR); Androgen Receptor Antagonists - administration & dosage; Androgen Receptor Antagonists - adverse effects; Androgen Receptor Antagonists - pharmacokinetics; Androgen Receptor Antagonists - pharmacology; Animals; Antineoplastic Agents - administration & dosage; Antineoplastic Agents - adverse effects; Antineoplastic Agents - pharmacokinetics; Antineoplastic Agents - pharmacology; AR degrader (SARD); Biomarkers, Tumor; castration-resistant prostate cancer (CRPC); Cell Line, Tumor; coactivator; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Resistance, Neoplasm - genetics; enzalutamide-resistant prostate cancer; Gene Expression; Humans; Male; Mice; Mutation; Phenylthiohydantoin - administration & dosage; Phenylthiohydantoin - adverse effects; Phenylthiohydantoin - analogs & derivatives; Phenylthiohydantoin - pharmacology; prostate cancer; Prostatic Neoplasms - drug therapy; Prostatic Neoplasms - metabolism; Prostatic Neoplasms - pathology; Proteasome Endopeptidase Complex - metabolism; Protein Binding; Proteolysis; Rats; Receptors, Androgen - genetics; Receptors, Androgen - metabolism; Signal Transduction - drug effects; Ubiquitin - metabolism; Xenograft Model Antitumor Assays
• ISSN: 1078-0432; 1557-3265
• DOI: 10.1158/1078-0432.CCR-19-1458

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. 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. UT-34 inhibits the wild-type and LBD-mutant ARs comparably and inhibits the proliferation and 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.