Rational design of original fused-cycle selective inhibitors of tryptophan 2,3-dioxygenase
| Autor: | Arina Kozlova, Benoît Van den Eynde, Raphaël Frédérick, Simon Klaessens, Léopold Thabault, Caroline Mathieu, Vincent Stroobant, Maxime Liberelle, Luc Pilotte, Julien R. C. Prevost |
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| Přispěvatelé: | UCL - SSS/LDRI - Louvain Drug Research Institute, UCL - SSS/DDUV/GECE - Génétique cellulaire |
| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
chemistry.chemical_classification
Kynurenine pathway Dose-Response Relationship Drug Molecular Structure biology Chemistry Catabolism Tryptophan Rational design Active site Triazoles Tryptophan Oxygenase Molecular Docking Simulation Structure-Activity Relationship Enzyme Biochemistry Drug Design Drug Discovery Cancer cell Tumor Cells Cultured biology.protein Humans Molecular Medicine Structure–activity relationship Enzyme Inhibitors |
| Zdroj: | Journal of Medicinal Chemistry, (2021) |
| Popis: | Tryptophan 2,3-dioxygenase (TDO2) is a heme-containing enzyme constitutively expressed at high concentrations in the liver and responsible for l-tryptophan (l-Trp) homeostasis. Expression of TDO2 in cancer cells results in the inhibition of immune-mediated tumor rejection due to an enhancement of l-Trp catabolism via the kynurenine pathway. In the study herein, we disclose a new 6-(1H-indol-3-yl)-benzotriazole scaffold of TDO2 inhibitors developed through rational design, starting from existing inhibitors. Rigidification of the initial scaffold led to the synthesis of stable compounds displaying a nanomolar cellular potency and a better understanding of the structural modulations that can be accommodated inside the active site of hTDO2. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
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