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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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    References listed on IDEAS

    as
    1. 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.
    2. Shanique Alabi & Saul Jaime-Figueroa & Zhan Yao & Yijun Gao & John Hines & Kusal T. G. Samarasinghe & Lea Vogt & Neal Rosen & Craig M. Crews, 2021. "Mutant-selective degradation by BRAF-targeting PROTACs," Nature Communications, Nature, vol. 12(1), pages 1-11, December.
    3. Mary E. Matyskiela & Gang Lu & Takumi Ito & Barbra Pagarigan & Chin-Chun Lu & Karen Miller & Wei Fang & Nai-Yu Wang & Derek Nguyen & Jack Houston & Gilles Carmel & Tam Tran & Mariko Riley & Lyn’Al Nos, 2016. "A novel cereblon modulator recruits GSPT1 to the CRL4CRBN ubiquitin ligase," Nature, Nature, vol. 535(7611), pages 252-257, July.
    4. Maximilian Benz & Mijanur R. Molla & Alexander Böser & Alisa Rosenfeld & Pavel A. Levkin, 2019. "Marrying chemistry with biology by combining on-chip solution-based combinatorial synthesis and cellular screening," Nature Communications, Nature, vol. 10(1), pages 1-10, December.
    5. Jian An & Charles M. Ponthier & Ragna Sack & Jan Seebacher & Michael B. Stadler & Katherine A. Donovan & Eric S. Fischer, 2017. "pSILAC mass spectrometry reveals ZFP91 as IMiD-dependent substrate of the CRL4CRBN ubiquitin ligase," Nature Communications, Nature, vol. 8(1), pages 1-11, August.
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