Selectively targeting prostate cancer with antiandrogen equipped histone deacetylase inhibitors

ACS Chem Biol. 2013 Nov 15;8(11):2550-60. doi: 10.1021/cb400542w. Epub 2013 Sep 20.


Diverse cellular processes relevant to cancer progression are regulated by the acetylation status of proteins. Among such processes is chromatin remodeling via histone proteins, controlled by opposing histone deacetylase (HDAC) and histone acetyltransferase (HAT) enzymes. Histone deacetylase inhibitors (HDACi) show great promise in preclinical cancer models, but clinical trials treating solid tumors have failed to improve patient survival. This is due in part to an inability of HDACi to effectively accumulate in cancerous cells. To address this problem we designed HDACi with secondary pharmacophores to facilitate selective accumulation in malignant cells. We present the first example of HDACi compounds targeted to prostate tumors by equipping them with the additional ability to bind the androgen receptor (AR) with nonsteroidal antiandrogen moieties. Leads among these new dual-acting molecules bind to the AR and halt AR transcriptional activity at lower concentrations than clinical antiandrogens. They inhibit key isoforms of HDAC with low nanomolar potency. Fluorescent microscopy reveals varying degrees of AR nuclear localization in response to these compounds that correlates with their HDAC activity. These biological properties translate into potent anticancer activity against hormone-dependent (AR+) LNCaP and to a lesser extent against hormone-independent (AR-) DU145 prostate cancer, while having greatly reduced toxicity in noncancerous cells. This illustrates that engaging multiple biological targets with a single chemical probe can achieve both potent and cell-type-selective responses.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Androgen Antagonists / chemical synthesis
  • Androgen Antagonists / chemistry
  • Androgen Antagonists / pharmacology
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Crystallography, X-Ray
  • Drug Delivery Systems*
  • Histone Deacetylase Inhibitors / chemical synthesis
  • Histone Deacetylase Inhibitors / chemistry
  • Histone Deacetylase Inhibitors / pharmacology*
  • Humans
  • Inhibitory Concentration 50
  • Male
  • Microscopy, Confocal
  • Models, Biological
  • Prostatic Neoplasms / drug therapy*
  • Prostatic Neoplasms / metabolism
  • Receptors, Androgen / metabolism


  • Androgen Antagonists
  • Histone Deacetylase Inhibitors
  • Receptors, Androgen