Metabolically stable diphenylamine derivatives suppress androgen receptor and BET protein in prostate cancer

Biochem Pharmacol. 2020 Jul:177:113946. doi: 10.1016/j.bcp.2020.113946. Epub 2020 Apr 2.

Abstract

Androgen receptor (AR) is a crucial driver of prostate cancer (PC). AR-relevant resistance remains a major challenge in castration-resistant prostate cancer (CRPC). Bromodomain and extra-terminal domain (BET) family are critical AR coregulators. Here, we developed several diphenylamine derivatives and identified compound 7d that disrupted the functions of AR and BET family in prostate cancer and exhibited favorable metabolic stability in vitro and high drug exposure in vivo. We showed 7d not only bound to AR, suppressed transactivation of wild-type AR (wt-AR) and the mutant that mediates Enzalutamide resistance, but also reduced c-Myc protein expression through BET inhibition. In addition, 7d inhibited the proliferation of AR-positive PC cells with favorable selectivity and suppressed AR-V7-expressing VCaP and 22Rv1 xenografts growth in vivo. Collectively, these results indicate the potential of lead compound 7d as an orally available AR and BET inhibitor to treat CRPC and overcome antiandrogen resistance.

Keywords: Androgen receptor; Antiandrogen resistance; Bromodomain and extra-terminal domain; Castration-resistant prostate cancer; Diphenylamine derivatives.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Androgen Receptor Antagonists / chemical synthesis
  • Androgen Receptor Antagonists / chemistry
  • Androgen Receptor Antagonists / pharmacology*
  • Animals
  • Cell Line, Tumor
  • Diphenylamine / chemical synthesis
  • Diphenylamine / chemistry
  • Diphenylamine / pharmacology*
  • HEK293 Cells
  • HT29 Cells
  • Humans
  • Male
  • Mice, Inbred BALB C
  • Mice, Nude
  • Models, Chemical
  • Molecular Structure
  • PC-3 Cells
  • Prostatic Neoplasms / drug therapy*
  • Prostatic Neoplasms / metabolism
  • Proteins / antagonists & inhibitors*
  • Proteins / metabolism
  • Receptors, Androgen / metabolism*
  • Xenograft Model Antitumor Assays / methods*

Substances

  • Androgen Receptor Antagonists
  • Proteins
  • Receptors, Androgen
  • bromodomain and extra-terminal domain protein, human
  • Diphenylamine