Chem-seq permits identification of genomic targets of drugs against androgen receptor regulation selected by functional phenotypic screens

Chunyu Jin, Liuqing Yang, Min Xie, Chunru Lin, Daria Merkurjev, Joy C. Yang, Bogdan Tanasa, Soohwan Oh, Jie Zhang, Kenneth A. Ohgi, Hongyan Zhou, Wenbo Li, Christopher P Evans, Sheng Ding, Michael G. Rosenfeld

Research output: Contribution to journalArticle

29 Citations (Scopus)

Abstract

Understanding the mechanisms by which compounds discovered using cell-based phenotypic screening strategies might exert their effects would be highly augmented by new approaches exploring their potential interactions with the genome. For example, altered androgen receptor (AR) transcriptional programs, including castration resistance and subsequent chromosomal translocations, play key roles in prostate cancer pathological progression, making the quest for identification of new therapeutic agents and an understanding of their actions a continued priority. Here we report an approach that has permitted us to uncover the sites and mechanisms of action of a drug, referred to as "SD70," initially identified by phenotypic screening for inhibitors of ligand and genotoxic stress-induced translocations in prostate cancer cells. Based on synthesis of a derivatized form of SD70 that permits its application for a ChIP-sequencing-like approach, referred to as "Chem-seq," we were next able to efficiently map the genome-wide binding locations of this small molecule, revealing that it largely colocalized with AR on regulatory enhancers. Based on these observations, we performed the appropriate global analyses to ascertain that SD70 inhibits the androgen-dependent AR program, and prostate cancer cell growth, acting, at least in part, by functionally inhibiting the Jumonji domain-containing demethylase, KDM4C. Global location of candidate drugs represents a powerful strategy for new drug development by mapping genomewide location of small molecules, a powerful adjunct to contemporary drug development strategies.

Original languageEnglish (US)
Pages (from-to)9235-9240
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume111
Issue number25
DOIs
StatePublished - Jun 24 2014

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Androgen Receptors
Prostatic Neoplasms
Pharmaceutical Preparations
Genome
Genetic Translocation
Castration
Androgens
DNA Damage
Ligands
Growth
Therapeutics

Keywords

  • Histone demethylase
  • Transcription

ASJC Scopus subject areas

  • General

Cite this

Chem-seq permits identification of genomic targets of drugs against androgen receptor regulation selected by functional phenotypic screens. / Jin, Chunyu; Yang, Liuqing; Xie, Min; Lin, Chunru; Merkurjev, Daria; Yang, Joy C.; Tanasa, Bogdan; Oh, Soohwan; Zhang, Jie; Ohgi, Kenneth A.; Zhou, Hongyan; Li, Wenbo; Evans, Christopher P; Ding, Sheng; Rosenfeld, Michael G.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 111, No. 25, 24.06.2014, p. 9235-9240.

Research output: Contribution to journalArticle

Jin, C, Yang, L, Xie, M, Lin, C, Merkurjev, D, Yang, JC, Tanasa, B, Oh, S, Zhang, J, Ohgi, KA, Zhou, H, Li, W, Evans, CP, Ding, S & Rosenfeld, MG 2014, 'Chem-seq permits identification of genomic targets of drugs against androgen receptor regulation selected by functional phenotypic screens', Proceedings of the National Academy of Sciences of the United States of America, vol. 111, no. 25, pp. 9235-9240. https://doi.org/10.1073/pnas.1404303111
Jin, Chunyu ; Yang, Liuqing ; Xie, Min ; Lin, Chunru ; Merkurjev, Daria ; Yang, Joy C. ; Tanasa, Bogdan ; Oh, Soohwan ; Zhang, Jie ; Ohgi, Kenneth A. ; Zhou, Hongyan ; Li, Wenbo ; Evans, Christopher P ; Ding, Sheng ; Rosenfeld, Michael G. / Chem-seq permits identification of genomic targets of drugs against androgen receptor regulation selected by functional phenotypic screens. In: Proceedings of the National Academy of Sciences of the United States of America. 2014 ; Vol. 111, No. 25. pp. 9235-9240.
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