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

ABSTRACT: 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.

SUBMITTER: Johnson JK

PROVIDER: S-EPMC4983742 | biostudies-literature | 2016 Aug

REPOSITORIES: biostudies-literature

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

Johnson James K JK Skoda Erin M EM Zhou Jianhua J Parrinello Erica E Wang Dan D O'Malley Katherine K Eyer Benjamin R BR Kazancioglu Mustafa M Eisermann Kurtis K Johnston Paul A PA Nelson Joel B JB Wang Zhou Z Wipf Peter P

ACS medicinal chemistry letters 20160527 8

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 ...[more]

PMID: 27563404

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