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A combinatorial screen of the CLOUD uncovers a synergy targeting the androgen receptor
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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.
National Category
Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy) Cancer and Oncology
Identifiers
URN: urn:nbn:se:umu:diva-137623DOI: 10.1038/nchembio.2382ISI: 000403673700014PubMedID: 28530711OAI: oai:DiVA.org:umu-137623DiVA: diva2:1127763
Available from: 2017-07-19 Created: 2017-07-19 Last updated: 2017-07-19Bibliographically approved

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Stattin, Pär
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