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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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