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Translation Termination Factor GSPT1 Is a Phenotypically Relevant Off-Target of Heterobifunctional Phthalimide Degraders

  • Mette Ishoey
    Mette Ishoey
    Department of Medical Oncology, Dana−Farber Cancer Institute, Boston, Massachusetts 02115, United States
    More by Mette Ishoey
  • Someth Chorn
    Someth Chorn
    CeMM Research Center for Molecular Medicine of the Austrian Academy of Science, Lazarettgasse 14, AKH Bt. 25.3, 1090 Vienna, Austria
    More by Someth Chorn
  • Natesh Singh
    Natesh Singh
    University of Vienna, Department of Pharmaceutical Chemistry, Althanstrasse 14, 1090 Vienna, Austria
    More by Natesh Singh
  • Martin G. Jaeger
    Martin G. Jaeger
    CeMM Research Center for Molecular Medicine of the Austrian Academy of Science, Lazarettgasse 14, AKH Bt. 25.3, 1090 Vienna, Austria
  • Matthias Brand
    Matthias Brand
    CeMM Research Center for Molecular Medicine of the Austrian Academy of Science, Lazarettgasse 14, AKH Bt. 25.3, 1090 Vienna, Austria
  • Joshiawa Paulk
    Joshiawa Paulk
    Department of Medical Oncology, Dana−Farber Cancer Institute, Boston, Massachusetts 02115, United States
    Novartis Institutes for Biomedical Research, Cambridge, Massachusetts 02139, United States
  • Sophie Bauer
    Sophie Bauer
    CeMM Research Center for Molecular Medicine of the Austrian Academy of Science, Lazarettgasse 14, AKH Bt. 25.3, 1090 Vienna, Austria
    More by Sophie Bauer
  • Michael A. Erb
    Michael A. Erb
    Department of Medical Oncology, Dana−Farber Cancer Institute, Boston, Massachusetts 02115, United States
  • Katja Parapatics
    Katja Parapatics
    CeMM Research Center for Molecular Medicine of the Austrian Academy of Science, Lazarettgasse 14, AKH Bt. 25.3, 1090 Vienna, Austria
  • André C. Müller
    André C. Müller
    CeMM Research Center for Molecular Medicine of the Austrian Academy of Science, Lazarettgasse 14, AKH Bt. 25.3, 1090 Vienna, Austria
  • Keiryn L. Bennett
    Keiryn L. Bennett
    CeMM Research Center for Molecular Medicine of the Austrian Academy of Science, Lazarettgasse 14, AKH Bt. 25.3, 1090 Vienna, Austria
  • Gerhard F. Ecker
    Gerhard F. Ecker
    University of Vienna, Department of Pharmaceutical Chemistry, Althanstrasse 14, 1090 Vienna, Austria
  • James E. Bradner*
    James E. Bradner
    Department of Medical Oncology, Dana−Farber Cancer Institute, Boston, Massachusetts 02115, United States
    Novartis Institutes for Biomedical Research, Cambridge, Massachusetts 02139, United States
    *Address: Novartis Institutes for Biomedical Research, 181 Massachusetts Avenue, Cambridge, MA 02139, USA. Tel.: 617-871-8800. E-mail: [email protected] (J. E. Bradner).
  • , and 
  • Georg E. Winter*
    Georg E. Winter
    CeMM Research Center for Molecular Medicine of the Austrian Academy of Science, Lazarettgasse 14, AKH Bt. 25.3, 1090 Vienna, Austria
    *Address: CeMM Research Center for Molecular Medicine of the Austrian Academy of Science Lazarettgasse 14, AKH Bt. 25.3 Vienna, Austria. Tel.: +43-1-40160-70031. E-mail: [email protected] (G. E. Winter).
Cite this: ACS Chem. Biol. 2018, 13, 3, 553–560
Publication Date (Web):January 22, 2018
Copyright © 2018 American Chemical Society

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    Abstract Image

    Protein degradation is an emerging therapeutic strategy with a unique molecular pharmacology that enables the disruption of all functions associated with a target. This is particularly relevant for proteins depending on molecular scaffolding, such as transcription factors or receptor tyrosine kinases (RTKs). To address tractability of multiple RTKs for chemical degradation by the E3 ligase CUL4-RBX1-DDB1-CRBN (CRL4CRBN), we synthesized a series of phthalimide degraders based on the promiscuous kinase inhibitors sunitinib and PHA665752. While both series failed to induce degradation of their consensus targets, individual molecules displayed pronounced efficacy in leukemia cell lines. Orthogonal target identification supported by molecular docking led us to identify the translation termination factor G1 to S phase transition 1 (GSPT1) as a converging off-target, resulting from inadvertent E3 ligase modulation. This research highlights the importance of monitoring degradation events that are independent of the respective targeting ligand as a unique feature of small-molecule degraders.

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    Supporting Information

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    The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acschembio.7b00969.

    • Supplementary Figures 1–3, Supplementary Tables 1–2, as well as experimental details and synthetic procedures (PDF)

    • RNA-seq values (FPKM) of individual drug-treated biological replicates (Supplementary Table 3) (XLSX)

    • KinomeScan MI-389 (Supplementary Table 4) (XLSX)

    • Chemoproteomics (Supplementary Table 5) (XLS)

    • Expression Proteomics (Supplementary Table 6) (XLSX)

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