University of Pennsylvania

Vanderbilt University

Trevor M Penning

Adegoke O Adeniji

Lawrence J Marnett

Michael C Byrns

Andy J Liedtke

Joseph W Ricigliano

Jeffrey Winkler

Barry Twenter

Leslie J Askonas

Michael C Burns

Provided are compositions for inhibiting a biological activity of an aldo-keto reductase family 1, member C3 (AKR1C3) polypeptide. In some embodiments, the compositions are indomethacin derivatives that are AKR1C3-specific inhibitors. Also provided are methods for producing disclosed indomethacin derivatives that substantially lack cyclooxygenase inhibitory activity but that have AKR1C3 inhibitory activity, methods for inhibiting AKR1C3 polypeptide biological activities, and methods for treating prostate tumors in subjects.

Indomethacin analogs for the treatment of castrate-resistant prostate cancer

The invention includes 2-&#x3b2;-naphthyl-acetic acid derivatives, which are selective AKR1C3 inhibitors. In certain embodiments, the compounds of the invention are (R)-naproxen analogs. The invention further includes methods of treating cancer, such as prostate cancer and/or castration-resistant prostate cancer, using at least one compound of the invention.

2-beta-naphthyl-acetic acid analogs as AKR1C3 inhibitors and methods of using same

The invention includes compositions comprising selective AKR1C3 inhibitors. The invention also includes compositions comprising bifunctional AKR1C3 inhibitors and selective androgen receptor modulators. The invention further includes methods of treatment using the compositions of the invention.

Bifunctional AKR1C3 inhibitors/androgen receptor modulators and methods of use thereof

Provided are compositions for inhibiting a biological activity of an aldoketo reductase family 1, member C3 (AKR1 C3) polypeptide. In some embodiments, the compositions are indomethacin derivatives that are AKR1 C3-specific inhibitors. Also provided are methods for producing disclosed indomethacin derivatives that substantially lack cyclooxygenase inhibitory activity but that have AKR1C3 inhibitory activity, methods for inhibiting AKR1C3 polypeptide biological activities, and methods for treating prostate tumors in subjects.

Compounds such as 1-(4'-nitrophenyl)-2-propen-1-ol are disclosed which are non-steroidal mechanism-based inactivators of rat liver 3.alpha.-hydroxysteroid dehydrogenase. The corresponding ketones are time dependent inactivators of cyclooxygenase (PGH.sub.2 -synthase).

Non-steroid and non-prostanoid inhibitors of steroid and prostaglandin

Irreversible ligands for nonsteroidal antiinflammatory drug and

Compounds, such as 1-(4'-nitrophenyl)-2-propen-1-ol, are disclosed which are highly selective non-steroidal suicide substrates for rat liver 3.alpha.-hydroxysteroid dehydrogenase.

Non-steroidal suicide substrates of hydroxysteroid dehydrogenase

Compounds such as 1-(4-bromoacetamidobenzyl)-5-methoxy-2-methylindole-3-acetic acid, N-(4-bromoacetamidophenyl) anthranilic acid and N-(3-bromoacetamidophenyl) anthranilic acid function as irreversible ligands for nonsteroidal antiinflammatory drug (NSAID) and prostaglandin binding sites. It is therefore expected that these compounds, and analogs thereof, will have utility as anti-inflammatory drugs, as affinity labeling agents and as ligands for use in affinity chromatography.

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Springfield, PA, United States of America

Trevor M Penning