Discovery of novel biphenyl derivatives as androgen receptor degraders for the treatment of enzalutamide-resistant prostate cancer

Bioorg Chem. 2024 Jul:148:107433. doi: 10.1016/j.bioorg.2024.107433. Epub 2024 May 7.

Abstract

Second-generation AR antagonists, such as enzalutamide, are the primary therapeutic agents for advanced prostate cancer. However, the development of both primary and secondary drug resistance leads to treatment failures and patient mortality. Bifunctional agents that simultaneously antagonize and degrade AR block the AR signaling pathway more completely and exhibit excellent antiproliferative activity against wild-type and drug-resistant prostate cancer cells. Here, we reported the discovery and optimization of a series of biphenyl derivatives as androgen receptor antagonists and degraders. These biphenyl derivatives exhibited potent antiproliferative activity against LNCaP and 22Rv1 cells. Our discoveries enrich the diversity of small molecule AR degraders and offer insights for the development of novel AR degraders for the treatment of enzalutamide-resistant prostate cancer.

Keywords: Androgen receptor; Biphenyl derivatives; Degraders; Prostate cancer.

MeSH terms

  • Androgen Receptor Antagonists* / chemical synthesis
  • Androgen Receptor Antagonists* / chemistry
  • Androgen Receptor Antagonists* / pharmacology
  • Androgen Receptor Antagonists* / therapeutic use
  • Antineoplastic Agents* / chemical synthesis
  • Antineoplastic Agents* / chemistry
  • Antineoplastic Agents* / pharmacology
  • Benzamides* / chemical synthesis
  • Benzamides* / chemistry
  • Benzamides* / pharmacology
  • Biphenyl Compounds* / antagonists & inhibitors
  • Biphenyl Compounds* / pharmacology
  • Cell Line, Tumor
  • Cell Proliferation* / drug effects
  • Dose-Response Relationship, Drug
  • Drug Discovery
  • Drug Resistance, Neoplasm* / drug effects
  • Drug Screening Assays, Antitumor
  • Humans
  • Male
  • Molecular Structure
  • Nitriles* / chemistry
  • Nitriles* / pharmacology
  • Phenylthiohydantoin* / analogs & derivatives
  • Phenylthiohydantoin* / chemistry
  • Phenylthiohydantoin* / pharmacology
  • Prostatic Neoplasms* / drug therapy
  • Prostatic Neoplasms* / metabolism
  • Prostatic Neoplasms* / pathology
  • Receptors, Androgen* / metabolism
  • Structure-Activity Relationship

Substances

  • Benzamides
  • Nitriles
  • enzalutamide
  • Phenylthiohydantoin
  • Biphenyl Compounds
  • Receptors, Androgen
  • Antineoplastic Agents
  • Androgen Receptor Antagonists
  • biphenyl
  • AR protein, human