High-throughput screen identifies novel inhibitors of cancer biomarker α-methylacyl coenzyme A racemase (AMACR/P504S)

Brice A.P. Wilson, Haofan Wang, Benjamin A. Nacev, Ronnie C. Mease, Jun O. Liu, Martin G. Pomper, William B. Isaacs

Research output: Contribution to journalArticlepeer-review

38 Scopus citations


α-methylacyl coenzyme A racemase (AMACR) is a metabolic enzyme whose overexpression has been shown to be a diagnostic indicator of prostatic adenocarcinoma and other solid tumors. Here, we confirm that attenuation of AMACR expression diminishes the growth of prostate cancer cell lines by using stably expressed short-hairpin RNA constructs. This observation strongly suggests that the AMACR enzyme may be a target for therapeutic inhibition in prostate cancer. To this end, we report here a novel assay capable of screening libraries of diverse small molecules for inhibitors of AMACR activity. This assay facilitated the screening of approximately 5,000 unique compounds and the discovery of 7 distinct chemical entities capable of inhibiting AMACR at low micromolar concentrations. The most potent inhibitor discovered is the selenoorganic compound ebselen oxide [inhibitory concentration (IC 50): 0.80 μmol/L]. The parent compound, ebselen (IC50: 2.79 μmol/L), is a covalent inactivator of AMACR (KI(inact): 24 μmol/L). Two of the AMACR inhibitors are selectively toxic to prostate cancer cell lines (LAPC4/LNCaP/PC3) that express AMACR compared to a normal prostate fibroblast cell line (WPMY1) that does not express the protein. This report shows the first high-throughput screen for the discovery of novel AMACR inhibitors, characterizes the first nonsubstrate-based inhibitors, and validates that AMACR is a viable chemotherapeutic target in vitro.

Original languageEnglish (US)
Pages (from-to)825-838
Number of pages14
JournalMolecular cancer therapeutics
Issue number5
StatePublished - May 2011

ASJC Scopus subject areas

  • Oncology
  • Cancer Research


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