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Direct-to-biology, automated, nano-scale synthesis, and phenotypic screening-enabled E3 ligase modulator discovery

Author

Listed:
  • Zefeng Wang

    (University of Groningen, Department of Drug Design)

  • Shabnam Shaabani

    (University of Groningen, Department of Drug Design)

  • Xiang Gao

    (University Hospital Ulm)

  • Yuen Lam Dora Ng

    (corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin)

  • Valeriia Sapozhnikova

    (corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin
    German Cancer Consortium (DKTK) partner site Berlin and German Cancer Research Center (DKFZ)
    Max Delbrück Center for Molecular Medicine)

  • Philipp Mertins

    (Max Delbrück Center for Molecular Medicine
    Berlin Institute of Health)

  • Jan Krönke

    (corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin
    German Cancer Consortium (DKTK) partner site Berlin and German Cancer Research Center (DKFZ))

  • Alexander Dömling

    (University of Groningen, Department of Drug Design
    Palackӯ University in Olomouc)

Abstract

Thalidomide and its analogs are molecular glues (MGs) that lead to targeted ubiquitination and degradation of key cancer proteins via the cereblon (CRBN) E3 ligase. Here, we develop a direct-to-biology (D2B) approach for accelerated discovery of MGs. In this platform, automated, high throughput, and nano scale synthesis of hundreds of pomalidomide-based MGs was combined with rapid phenotypic screening, enabling an unprecedented fast identification of potent CRBN-acting MGs. The small molecules were further validated by degradation profiling and anti-cancer activity. This revealed E14 as a potent MG degrader targeting IKZF1/3, GSPT1 and 2 with profound effects on a panel of cancer cells. In a more generalized view, integration of automated, nanoscale synthesis with phenotypic assays has the potential to accelerate MGs discovery.

Suggested Citation

  • Zefeng Wang & Shabnam Shaabani & Xiang Gao & Yuen Lam Dora Ng & Valeriia Sapozhnikova & Philipp Mertins & Jan Krönke & Alexander Dömling, 2023. "Direct-to-biology, automated, nano-scale synthesis, and phenotypic screening-enabled E3 ligase modulator discovery," Nature Communications, Nature, vol. 14(1), pages 1-12, December.
    • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-43614-3
    DOI: 10.1038/s41467-023-43614-3
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    3. Maximilian Benz & Mijanur R. Molla & Alexander Böser & Alisa Rosenfeld & Pavel A. Levkin, 2019. "Author Correction: Marrying chemistry with biology by combining on-chip solution-based combinatorial synthesis and cellular screening," Nature Communications, Nature, vol. 10(1), pages 1-1, December.
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