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Nat Chem Biol. 2017 Jul;13(7):771-778. doi: 10.1038/nchembio.2382. Epub 2017 May 22.

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

Author information

1
CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria.
2
Christian Doppler Laboratory for Chemical Epigenetics and Anti infectives, CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria.
3
Christian Doppler Laboratory for Molecular Stress Research in Peritoneal Dialysis, Department of Pediatrics and Adolescent Medicine, Medical University of Vienna, Vienna, Austria.
4
Department of Surgery and Perioperative Sciences, Urology and Andrology, Umeå University Hospital, Umeå, Sweden.
5
Department of Surgical Sciences, Uppsala University, Uppsala, Sweden.
6
Enamine Ltd., Kiev, Ukraine.
7
Department of Laboratory Medicine, Medical University of Vienna, Vienna, Austria.
8
Max Planck Institute for Informatics, Saarland Informatics Campus, Saarbrücken, Germany.

Abstract

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.

PMID:
28530711
DOI:
10.1038/nchembio.2382
[Indexed for MEDLINE]

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