1. Academic Validation
  2. 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. jan.kroenke@charite.de.
  • 8 German Cancer Consortium (DKTK) partner site Berlin and German Cancer Research Center (DKFZ), Heidelberg, Germany. jan.kroenke@charite.de.
  • 9 University of Groningen, Department of Drug Design, A. Deusinglaan 1, 9713 AV, Groningen, The Netherlands. alexander.domling@upol.cz.
  • 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. alexander.domling@upol.cz.
  • # Contributed equally.
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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