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A combinatorial screen of the CLOUD uncovers a synergy targeting the androgen receptor
Austrian Acad Sci, CeMM Res Ctr Mol Med, Vienna, Austria.;Inst Canc Res, Canc Res UK Canc Therapeut Unit, London, England..
Austrian Acad Sci, CeMM Res Ctr Mol Med, Vienna, Austria..
Austrian Acad Sci, CeMM Res Ctr Mol Med, Vienna, Austria.;Univ Innsbruck Hosp, Dept Pharm, Innsbruck, Austria..
Austrian Acad Sci, CeMM Res Ctr Mol Med, Vienna, Austria.;Chem Comp Grp Inc, Cologne, Germany..
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2017 (English)In: Nature Chemical Biology, ISSN 1552-4450, E-ISSN 1552-4469, Vol. 13, no 7, 771-778 p.Article in journal (Refereed) Published
Abstract [en]

Approved drugs are invaluable tools to study biochemical pathways, and further characterization of these compounds may lead to repurposing of single drugs or combinations. Here we describe a collection of 308 small molecules representing the diversity of structures and molecular targets of all FDA-approved chemical entities. The CeMM Library of Unique Drugs (CLOUD) covers prodrugs and active forms at pharmacologically relevant concentrations and is ideally suited for combinatorial studies. We screened pairwise combinations of CLOUD drugs for impairment of cancer cell viability and discovered a synergistic interaction between flutamide and phenprocoumon (PPC). The combination of these drugs modulates the stability of the androgen receptor (AR) and resensitizes AR-mutant prostate cancer cells to flutamide. Mechanistically, we show that the AR is a substrate for gamma-carboxylation, a post-translational modification inhibited by PPC. Collectively, our data suggest that PPC could be repurposed to tackle resistance to antiandrogens in prostate cancer patients.

Place, publisher, year, edition, pages
NATURE PUBLISHING GROUP , 2017. Vol. 13, no 7, 771-778 p.
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Biochemistry and Molecular Biology
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URN: urn:nbn:se:uu:diva-329630DOI: 10.1038/nchembio.2382ISI: 000403673700014PubMedID: 28530711OAI: oai:DiVA.org:uu-329630DiVA: diva2:1144000
Available from: 2017-09-25 Created: 2017-09-25 Last updated: 2017-09-25Bibliographically approved

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Stattin, Pär

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