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.

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Acknowledgements

We thank M. Iskar (EMBL) and P. Bork (EMBL) for providing us with DIPS scores, R. Schüle (Albert-Ludwigs-University Freiburg, Germany) for LAPC4 cells, and G. Winter (CeMM) and G. Superti-Furga (CeMM) for thoughtful discussions and initializing synergy screenings at CeMM. S.K. acknowledges support by a Marie Curie Career Integration Grant, the Austrian Federal Ministry of Science, Research and Economy and the National Foundation for Research, Technology, and Development and the Austrian Science Fund (FWF): F4701-B20.

Author information

Author notes

    • Marco P Licciardello
    • , Patrick Markt
    • , Freya Klepsch
    • , Gerhard Dürnberger
    •  & Jacques Colinge

    Present addresses: Cancer Research UK Cancer Therapeutics Unit, The Institute of Cancer Research, London, UK (M.P.L.); Pharmacy Department, Innsbruck University Hospital, Innsbruck, Austria (P.M.); Chemical Computing Group, Inc., Cologne, Germany (F.K.); Gregor Mendel Institute, Vienna, Austria (G.D.); Faculté de Médecine, Université de Montpellier, and Institut de Recherche en Cancérologie de Montpellier, INSERM U1194, Institut régional du Cancer Montpellier, Montpellier, France (J.C.).

Affiliations

  1. CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria.

    • Marco P Licciardello
    • , Anna Ringler
    • , Patrick Markt
    • , Freya Klepsch
    • , Charles-Hugues Lardeau
    • , Sara Sdelci
    • , Erika Schirghuber
    • , André C Müller
    • , Michael Caldera
    • , Thomas Penz
    • , Michael Schuster
    • , Bernd Boidol
    • , Gerhard Dürnberger
    • , Jacques Colinge
    • , Christoph Bock
    • , Jörg Menche
    • , Keiryn L Bennett
    •  & Stefan Kubicek
  2. Christian Doppler Laboratory for Chemical Epigenetics and Anti infectives, CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria.

    • Charles-Hugues Lardeau
    • , Erika Schirghuber
    • , Bernd Boidol
    •  & Stefan Kubicek
  3. Christian Doppler Laboratory for Molecular Stress Research in Peritoneal Dialysis, Department of Pediatrics and Adolescent Medicine, Medical University of Vienna, Vienna, Austria.

    • Anja Wagner
    • , Rebecca Herzog
    •  & Klaus Kratochwill
  4. Department of Surgery and Perioperative Sciences, Urology and Andrology, Umeå University Hospital, Umeå, Sweden.

    • Yasin Folkvaljon
    •  & Pär Stattin
  5. Department of Surgical Sciences, Uppsala University, Uppsala, Sweden.

    • Pär Stattin
  6. Enamine Ltd., Kiev, Ukraine.

    • Vladimir Ivanov
  7. Department of Laboratory Medicine, Medical University of Vienna, Vienna, Austria.

    • Christoph Bock
  8. Max Planck Institute for Informatics, Saarland Informatics Campus, Saarbrücken, Germany.

    • Christoph Bock

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Contributions

P.M., F.K. and S.K. designed and assembled the CLOUD. M.P.L., F.K., C.-H.L. and S.K. designed and performed the screen of the CLOUD. M.P.L., F.K., M.C. and J.M. analyzed the data from the screen. M.P.L. and A.R. designed and performed viability, RT-qPCR, western blotting, immunoprecipitation and immunofluorescence experiments. S.S. performed immunofluorescence experiments. A.R. and E.S. designed and performed gene expression and immunoprecipitation experiments. A.R. and B.B. designed and performed knockdown experiments. A.C.M. and K.L.B. designed and performed proteomics experiments. A.W., R.H. and K.K. performed and analyzed 2D gel electrophoresis experiments. T.P., M.S. and C.B. performed and analyzed RNA-seq experiments. G.D. and J.C. performed DIPS score analyses. Y.F. and P.S. analyzed patient data in PCBaSe. V.I. synthesized, provided and quality controlled chemicals. M.P.L. and S.K. wrote the manuscript.

Competing interests

M.P.L. and S.K. have filed a patent based on findings described in this manuscript (WO2016170102 A1). V.I. is an employee of Enamine, Ltd and may also own shares in the company.

Corresponding author

Correspondence to Stefan Kubicek.

Supplementary information

PDF files

  1. 1.

    Supplementary Text and Figures

    Supplementary Results, Supplementary Tables 1–4 and Supplementary Figures 1–21

Excel files

  1. 1.

    Supplementary Data Set 1

    STEAM and CLOUD drugs.

  2. 2.

    Supplementary Data Set 2

    Data from CLOUD combinatorial screen.

  3. 3.

    Supplementary Data Set 3

    Synergies and antagonisms defined by both Bliss and Loewe scores.

About this article

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DOI

https://doi.org/10.1038/nchembio.2382

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