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

• Published in: ACS medicinal chemistry letters Vol. 7; no. 8; pp. 785 - 790
• Main Authors: Johnson, James K, Skoda, Erin M, Zhou, Jianhua, Parrinello, Erica, Wang, Dan, O’Malley, Katherine, Eyer, Benjamin R, Kazancioglu, Mustafa, Eisermann, Kurtis, Johnston, Paul A, Nelson, Joel B, Wang, Zhou, Wipf, Peter
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 11.08.2016; Amer Chemical Soc
• Subjects: Chemistry, Medicinal; Letter; Life Sciences & Biomedicine; Pharmacology & Pharmacy; Science & Technology; thioether isostere; isoxazoles; luciferase assay; CRPC; Androgen receptor; advanced prostate cancer; ANTIANDROGEN; MECHANISMS; DISCOVERY
• ISSN: 1948-5875; 1948-5875
• DOI: 10.1021/acsmedchemlett.6b00186

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.