Small Molecule Antagonists of the Nuclear Androgen Receptor for the Treatment of Castration-Resistant Prostate Cancer

After a high-throughput screening campaign identified thioether 1 as an antagonist of the nuclear androgen receptor, a zone model was developed for structure-activity relationship (SAR) purposes and analogues were synthesized and evaluated in a cell-based luciferase assay. A novel thioether isostere, cyclopropane (1S,2R)-27, showed the desired increased potency and structural properties (stereospecific SAR response, absence of a readily oxidized sulfur atom, low molecular weight, reduced number of flexible bonds and polar surface area, and drug-likeness score) in the prostate-specific antigen luciferase assay in C4-2-PSA-rl cells to qualify as a new lead structure for prostate cancer drug development.

ACS medicinal chemistry letters. 2016 May 27*** epublish ***

James K Johnson, Erin M Skoda, Jianhua Zhou, Erica Parrinello, Dan Wang, Katherine O'Malley, Benjamin R Eyer, Mustafa Kazancioglu, Kurtis Eisermann, Paul A Johnston, Joel B Nelson, Zhou Wang, Peter Wipf

Department of Chemistry, University of Pittsburgh , Pittsburgh, Pennsylvania 15260, United States., Department of Urology, University of Pittsburgh School of Medicine , Pittsburgh, Pennsylvania 15232, United States., Department of Pharmaceutical Sciences, University of Pittsburgh , Pittsburgh, Pennsylvania 15261, United States., Department of Chemistry, University of Pittsburgh, Pittsburgh, Pennsylvania 15260, United States; Department of Pharmaceutical Sciences, University of Pittsburgh, Pittsburgh, Pennsylvania 15261, United States.

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