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

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-resist...

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Bibliographic Details
Published in:Clinical cancer research 2019-11, Vol.25 (22), p.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: Article
Language:English
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
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Summary: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.
ISSN:1078-0432
1557-3265
DOI:10.1158/1078-0432.CCR-19-1458