Prospective discovery of small molecule enhancers of an E3 ligase-substrate interaction
| Autor: | Paul A. Barsanti, Joshua Taygerly, Kathleen Boyle, Kyle R. Simonetta, Stephanie L. Yung, Szerenke Kiss von Soly, Chris Padovani, Frank Kayser, Neil Bence, Anjanabha Saha, Stephen E. Basham, John Kuriyan, Mark Gallop, Thomas Cummins, Yan Lou, Michael Rape, Mario G. Cardozo |
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| Jazyk: | angličtina |
| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
Ubiquitin-Protein Ligases Science General Physics and Astronomy 02 engineering and technology General Biochemistry Genetics and Molecular Biology Article Substrate Specificity Small Molecule Libraries 03 medical and health sciences Ubiquitin MD Multidisciplinary Genetics Humans Phosphorylation lcsh:Science Enhancer beta Catenin chemistry.chemical_classification DNA ligase Substrate Interaction Multidisciplinary biology Drug discovery Rational design Ubiquitination General Chemistry 021001 nanoscience & nanotechnology beta-Transducin Repeat-Containing Proteins Small molecule Cell biology Ubiquitin ligase 030104 developmental biology HEK293 Cells chemistry 5.1 Pharmaceuticals Proteolysis biology.protein lcsh:Q Development of treatments and therapeutic interventions 0210 nano-technology Biotechnology Protein Binding |
| Zdroj: | Nature Communications, Vol 10, Iss 1, Pp 1-12 (2019) Nature Communications Nature communications, vol 10, iss 1 Simonetta, Kyle R; Taygerly, Joshua; Boyle, Kathleen; Basham, Stephen E; Padovani, Chris; Lou, Yan; et al.(2019). Prospective discovery of small molecule enhancers of an E3 ligase-substrate interaction.. Nature communications, 10(1), 1402. doi: 10.1038/s41467-019-09358-9. UC Berkeley: Retrieved from: http://www.escholarship.org/uc/item/26s7m3b9 |
| ISSN: | 2041-1723 |
| DOI: | 10.1038/s41467-019-09358-9. |
| Popis: | Protein–protein interactions (PPIs) governing the recognition of substrates by E3 ubiquitin ligases are critical to cellular function. There is significant therapeutic potential in the development of small molecules that modulate these interactions; however, rational design of small molecule enhancers of PPIs remains elusive. Herein, we report the prospective identification and rational design of potent small molecules that enhance the interaction between an oncogenic transcription factor, β-Catenin, and its cognate E3 ligase, SCFβ-TrCP. These enhancers potentiate the ubiquitylation of mutant β-Catenin by β-TrCP in vitro and induce the degradation of an engineered mutant β-Catenin in a cellular system. Distinct from PROTACs, these drug-like small molecules insert into a naturally occurring PPI interface, with contacts optimized for both the substrate and ligase within the same small molecule entity. The prospective discovery of ‘molecular glue’ presented here provides a paradigm for the development of small molecule degraders targeting hard-to-drug proteins. Directed protein degradation to target hard-to-drug proteins is a promising therapeutic approach. Here, the authors report the prospective discovery of small molecule “molecular glue” that inserts into a naturally occurring E3 ligase-substrate interface leading to degradation of substrate protein. |
| Databáze: | OpenAIRE |
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