A combinatorial screen of the CLOUD uncovers a synergy targeting the androgen receptor.

Autor: Licciardello MP; CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria., Ringler A; CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria., Markt P; CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria., Klepsch F; CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria., Lardeau CH; CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria.; Christian Doppler Laboratory for Chemical Epigenetics and Anti infectives, CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria., Sdelci S; CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria., Schirghuber E; CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria.; Christian Doppler Laboratory for Chemical Epigenetics and Anti infectives, CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria., Müller AC; CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria., Caldera M; CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria., Wagner A; Christian Doppler Laboratory for Molecular Stress Research in Peritoneal Dialysis, Department of Pediatrics and Adolescent Medicine, Medical University of Vienna, Vienna, Austria., Herzog R; Christian Doppler Laboratory for Molecular Stress Research in Peritoneal Dialysis, Department of Pediatrics and Adolescent Medicine, Medical University of Vienna, Vienna, Austria., Penz T; CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria., Schuster M; CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria., Boidol B; CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria.; Christian Doppler Laboratory for Chemical Epigenetics and Anti infectives, CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria., Dürnberger G; CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria., Folkvaljon Y; Department of Surgery and Perioperative Sciences, Urology and Andrology, Umeå University Hospital, Umeå, Sweden., Stattin P; Department of Surgery and Perioperative Sciences, Urology and Andrology, Umeå University Hospital, Umeå, Sweden.; Department of Surgical Sciences, Uppsala University, Uppsala, Sweden., Ivanov V; Enamine Ltd., Kiev, Ukraine., Colinge J; CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria., Bock C; CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria.; Department of Laboratory Medicine, Medical University of Vienna, Vienna, Austria.; Max Planck Institute for Informatics, Saarland Informatics Campus, Saarbrücken, Germany., Kratochwill K; Christian Doppler Laboratory for Molecular Stress Research in Peritoneal Dialysis, Department of Pediatrics and Adolescent Medicine, Medical University of Vienna, Vienna, Austria., Menche J; CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria., Bennett KL; CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria., Kubicek S; CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria.; Christian Doppler Laboratory for Chemical Epigenetics and Anti infectives, CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria.
Jazyk: angličtina
Zdroj: Nature chemical biology [Nat Chem Biol] 2017 Jul; Vol. 13 (7), pp. 771-778. Date of Electronic Publication: 2017 May 22.
DOI: 10.1038/nchembio.2382
Abstrakt: 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 γ-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.
Databáze: MEDLINE
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