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* (Corresponding Author)

*Corresponding author for this work

Research output: Contribution to journalArticle

5 Citations (Scopus)

Abstract

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.
Original languageEnglish
Pages (from-to)6764-6780
Number of pages17
JournalClinical Cancer Research
Volume25
Issue number22
Early online date17 Oct 2019
DOIs
Publication statusPublished - 15 Nov 2019

Keywords

  • prostate cancer
  • Castration-Resistant Prostate Cancer (CRPC)
  • androgen receptor (AR)
  • AR degrader (SARD)
  • coactivator
  • enzalutamide-resistant prostate cancer
  • PHOSPHORYLATION
  • CYP17A1 INHIBITOR
  • SPLICE VARIANT
  • ANTITUMOR-ACTIVITY
  • DIFFERENTIAL REGULATION
  • BREAST-CANCER
  • ANTIANDROGEN
  • GENE
  • INCREASED SURVIVAL
  • ABIRATERONE

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