Discovery of a novel AR/HDAC6 dual inhibitor for prostate cancer treatment

Aging (Albany NY). 2021 Feb 17;13(5):6982-6998. doi: 10.18632/aging.202554. Epub 2021 Feb 17.

Abstract

Androgen receptor (AR) and histone deacetylase 6 (HDAC6) are important targets for cancer therapy. Given that both AR antagonists and HDAC6 inhibitors modulate AR signaling, a novel AR/HDAC6 dual inhibitor is investigated for its anticancer effects in castration-resistant prostate cancer (CRPC). Zeta55 inhibits nuclear translocation of AR and suppresses androgen-induced PSA and TMPRSS2 expression. Meanwhile, Zeta55 selectively inhibits HDAC6 activity, leading to AR degradation. Zeta55 reduces the growth of AR-overexpressing VCaP prostate cancer cells both in vitro and in a CRPC xenograft model. These results provide preclinical proof of principle for Zeta55 as a promising therapeutic in prostate cancer treatment.

Keywords: HDAC6; Zeta55; androgen receptor; dual inhibitor; prostate cancer.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Active Transport, Cell Nucleus / drug effects
  • Androgen Receptor Antagonists / chemistry
  • Androgen Receptor Antagonists / pharmacology*
  • Animals
  • Histone Deacetylase 6 / antagonists & inhibitors*
  • Male
  • Mice
  • Mice, SCID
  • Prostate-Specific Antigen / drug effects
  • Prostatic Neoplasms, Castration-Resistant / drug therapy*
  • Serine Endopeptidases / drug effects

Substances

  • Androgen Receptor Antagonists
  • Serine Endopeptidases
  • TMPRSS2 protein, mouse
  • Prostate-Specific Antigen
  • Hdac6 protein, mouse
  • Histone Deacetylase 6