2. Academic Validation
  3. Direct-to-biology, automated, nano-scale synthesis, and phenotypic screening-enabled E3 ligase modulator discovery

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

  • Nat Commun. 2023 Dec 19;14(1):8437. doi: 10.1038/s41467-023-43614-3.
Zefeng Wang # 1,  Shabnam Shaabani # 1,  Xiang Gao # 2,  Yuen Lam Dora Ng 3,  Valeriia Sapozhnikova 3 4 5,  Philipp Mertins 5 6,  Jan Krönke 7 8,  Alexander Dömling 9 10
Affiliations

Affiliations

  • 1 University of Groningen, Department of Drug Design, A. Deusinglaan 1, 9713 AV, Groningen, The Netherlands.
  • 2 Department of Internal Medicine III, University Hospital Ulm, 89081, Ulm, Germany.
  • 3 Department of Hematology, Oncology and Cancer Immunology, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany.
  • 4 German Cancer Consortium (DKTK) partner site Berlin and German Cancer Research Center (DKFZ), Heidelberg, Germany.
  • 5 Max Delbrück Center for Molecular Medicine, Berlin, Germany.
  • 6 Berlin Institute of Health, Berlin, Germany.
  • 7 Department of Hematology, Oncology and Cancer Immunology, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany. [email protected].
  • 8 German Cancer Consortium (DKTK) partner site Berlin and German Cancer Research Center (DKFZ), Heidelberg, Germany. [email protected].
  • 9 University of Groningen, Department of Drug Design, A. Deusinglaan 1, 9713 AV, Groningen, The Netherlands. [email protected].
  • 10 Institute of Molecular and Translational Medicine, Faculty of Medicine and Dentistry and Czech Advanced Technology and Research Institute, Palackӯ University in Olomouc, Olomouc, Czech Republic. [email protected].
  • # Contributed equally.
PMID: 38114468 DOI: 10.1038/s41467-023-43614-3
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.

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