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

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Item Type:	Article
Title:	Direct-to-biology, automated, nano-scale synthesis, and phenotypic screening-enabled E3 ligase modulator discovery
Creators Name:	Wang, Z., Shaabani, S., Gao, X., Ng, Y.L.D., Sapozhnikova, V., Mertins, P., Krönke, J. and Dömling, A.
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.
Keywords:	Biology, Peptide Hydrolases, Proteolysis, Ubiquitin-Protein Ligases, Ubiquitination
Source:	Nature Communications
ISSN:	2041-1723
Publisher:	Nature Publishing Group
Volume:	14
Number:	1
Page Range:	8437
Date:	19 December 2023
Official Publication:	https://doi.org/10.1038/s41467-023-43614-3
PubMed:	View item in PubMed

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