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

Zefeng Wang, Shabnam Shaabani, Xiang Gao, Yuen Lam Dora Ng, Valeriia Sapozhnikova, Philipp Mertins, Jan Krönke () and Alexander Dömling ()
Additional contact information
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
Philipp Mertins: Max Delbrück Center for Molecular Medicine
Jan Krönke: corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin
Alexander Dömling: University of Groningen, Department of Drug Design

Nature Communications, 2023, vol. 14, issue 1, 1-12

Abstract: 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.

Date: 2023
References: View references in EconPapers View complete reference list from CitEc
Citations:

Downloads: (external link)
https://www.nature.com/articles/s41467-023-43614-3 Abstract (text/html)

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-43614-3

Ordering information: This journal article can be ordered from
https://www.nature.com/ncomms/

DOI: 10.1038/s41467-023-43614-3

Access Statistics for this article

Nature Communications is currently edited by Nathalie Le Bot, Enda Bergin and Fiona Gillespie

More articles in Nature Communications from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().