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Mol Cancer Ther. 2011 May;10(5):825-38. doi: 10.1158/1535-7163.MCT-10-0902. Epub 2011 Mar 25.

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

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Department of Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, MD, USA.


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 seleno-organic compound ebselen oxide [inhibitory concentration (IC(50)): 0.80 μmol/L]. The parent compound, ebselen (IC(50): 2.79 μmol/L), is a covalent inactivator of AMACR (K(I)((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.

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