title: Dose-dependent effects of small-molecule antagonists on the genomic landscape of androgen receptor binding.
abstract: BACKGROUND
  The androgen receptor plays a critical role throughout the progression of prostate cancer and is an important drug target for this disease. While chromatin immunoprecipitation coupled with massively parallel sequencing (ChIP-Seq) is becoming an essential tool for studying transcription and chromatin modification factors, it has rarely been employed in the context of drug discovery.
  
  
  RESULTS
  Here we report changes in the genome-wide AR binding landscape due to dose-dependent inhibition by drug-like small molecules using ChIP-Seq. Integration of sequence analysis, transcriptome profiling, cell viability assays and xenograft tumor growth inhibition studies enabled us to establish a direct cistrome-activity relationship for two novel potent AR antagonists. By selectively occupying the strongest binding sites, AR signaling remains active even when androgen levels are low, as is characteristic of first-line androgen ablation therapy. Coupled cistrome and transcriptome profiling upon small molecule antagonism led to the identification of a core set of AR direct effector genes that are most likely to mediate the activities of targeted agents: unbiased pathway mapping revealed that AR is a key modulator of steroid metabolism by forming a tightly controlled feedback loop with other nuclear receptor family members and this oncogenic effect can be relieved by antagonist treatment. Furthermore, we found that AR also has an extensive role in negative gene regulation, with estrogen (related) receptor likely mediating its function as a transcriptional repressor.
  
  
  CONCLUSIONS
  Our study provides a global and dynamic view of AR's regulatory program upon antagonism, which may serve as a molecular basis for deciphering and developing AR therapeutics.
authors: Oncology Research Unit, Pfizer Worldwide Research & Development, La Jolla Laboratories, San Diego, CA 92121, USA. Zhou.Zhu@pfizer.com
authors: Zhou
authors: Z
authors: Zhu
authors: Manli
authors: M
authors: Shi
authors: Wenyue
authors: W
authors: Hu
authors: Heather
authors: H
authors: Estrella
authors: Jon
authors: J
authors: Engebretsen
authors: Tim
authors: T
authors: Nichols
authors: David
authors: D
authors: Briere
authors: Natilie
authors: N
authors: Hosea
authors: Gerrit
authors: G
authors: Los
authors: Paul A
authors: PA
authors: Rejto
authors: Andrea
authors: A
authors: Fanjul
mesh_terms: D059002:Androgen Receptor Antagonists / Q000378:metabolism* / Q000627:therapeutic use / Q000633:toxicity; D000818:Animals; D001665:Binding Sites; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D047369:Chromatin Immunoprecipitation; D002874:Chromosome Mapping; D004305:Dose-Response Relationship, Drug; D006801:Humans; D008297:Male; D051379:Mice; D016513:Mice, SCID; D011471:Prostatic Neoplasms / Q000188:drug therapy; D011485:Protein Binding; D011944:Receptors, Androgen / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D017422:Sequence Analysis, DNA; D054852:Small Molecule Libraries / Q000378:metabolism* / Q000627:therapeutic use / Q000633:toxicity; D014183:Transplantation, Heterologous
chemical_list: D059002:Androgen Receptor Antagonists; D011944:Receptors, Androgen; D054852:Small Molecule Libraries