Article ; Online: Discovery of Small Molecule Interleukin 17A Inhibitors with Novel Binding Mode and Stoichiometry: Optimization of DNA-Encoded Chemical Library Hits to In Vivo Active Compounds.
Journal of medicinal chemistry
2024 Volume 67, Issue 8, Page(s) 6456–6494
Abstract: Dysregulation of IL17A drives numerous inflammatory and autoimmune disorders with inhibition of IL17A using antibodies proven as an effective treatment. Oral anti-IL17 therapies are an attractive alternative option, and several preclinical small molecule ...
| Abstract | Dysregulation of IL17A drives numerous inflammatory and autoimmune disorders with inhibition of IL17A using antibodies proven as an effective treatment. Oral anti-IL17 therapies are an attractive alternative option, and several preclinical small molecule IL17 inhibitors have previously been described. Herein, we report the discovery of a novel class of small molecule IL17A inhibitors, identified via a DNA-encoded chemical library screen, and their subsequent optimization to provide in vivo efficacious inhibitors. These new protein-protein interaction (PPI) inhibitors bind in a previously undescribed mode in the IL17A protein with two copies binding symmetrically to the central cavities of the IL17A homodimer. |
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| MeSH term(s) | Interleukin-17/metabolism ; Interleukin-17/antagonists & inhibitors ; Small Molecule Libraries/chemistry ; Small Molecule Libraries/pharmacology ; DNA/metabolism ; DNA/chemistry ; Humans ; Drug Discovery ; Animals ; Structure-Activity Relationship ; Protein Binding ; Mice | ||||||||||
| Chemical Substances | Interleukin-17 ; Small Molecule Libraries ; DNA (9007-49-2) ; IL17A protein, human | ||||||||||
| Language | English | ||||||||||
| Publishing date | 2024-04-04 | ||||||||||
| Publishing country | United States | ||||||||||
| Document type | Journal Article ; Research Support, Non-U.S. Gov't | ||||||||||
| ZDB-ID | 218133-2 | ||||||||||
| ISSN | 1520-4804 ; 0022-2623 | ||||||||||
| ISSN (online) | 1520-4804 | ||||||||||
| ISSN | 0022-2623 | ||||||||||
| DOI | 10.1021/acs.jmedchem.3c02397 | ||||||||||
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| Database | MEDical Literature Analysis and Retrieval System OnLINE |
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