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

Autor: Wang Z; University of Groningen, Department of Drug Design, A. Deusinglaan 1, 9713 AV, Groningen, The Netherlands., Shaabani S; University of Groningen, Department of Drug Design, A. Deusinglaan 1, 9713 AV, Groningen, The Netherlands., Gao X; Department of Internal Medicine III, University Hospital Ulm, 89081, Ulm, Germany., Ng YLD; Department of Hematology, Oncology and Cancer Immunology, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany., Sapozhnikova V; Department of Hematology, Oncology and Cancer Immunology, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany.; German Cancer Consortium (DKTK) partner site Berlin and German Cancer Research Center (DKFZ), Heidelberg, Germany.; Max Delbrück Center for Molecular Medicine, Berlin, Germany., Mertins P; Max Delbrück Center for Molecular Medicine, Berlin, Germany.; Berlin Institute of Health, Berlin, Germany., Krönke J; 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.; German Cancer Consortium (DKTK) partner site Berlin and German Cancer Research Center (DKFZ), Heidelberg, Germany. jan.kroenke@charite.de., Dömling A; University of Groningen, Department of Drug Design, A. Deusinglaan 1, 9713 AV, Groningen, The Netherlands. alexander.domling@upol.cz.; 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.
Jazyk: angličtina
Zdroj: Nature communications [Nat Commun] 2023 Dec 19; Vol. 14 (1), pp. 8437. Date of Electronic Publication: 2023 Dec 19.
DOI: 10.1038/s41467-023-43614-3
Abstrakt: 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.
(© 2023. The Author(s).)
Databáze: MEDLINE
Externí odkaz: