Tryptophan 2,3-dioxygenase (TDO) inhibitors. 3-(2-(pyridyl)ethenyl)indoles as potential anticancer immunomodulators
| Autor: | Pierre Larrieu, Eduard Dolusic, Laurence Moineaux, Lionel Pochet, Luc Pilotte, Raphaël Frédérick, Bernard Masereel, Johan Wouters, Benoît Van den Eynde, Vincent Stroobant, Didier Colau |
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| Jazyk: | angličtina |
| Rok vydání: | 2011 |
| Předmět: |
Indoles
Biological Availability Antineoplastic Agents Pharmacology Tryptophan 2 3 dioxygenase Immune tolerance Cell Line Mice Structure-Activity Relationship Neoplasms Drug Discovery Structure–activity relationship Animals Humans Immunologic Factors Enzyme Inhibitors Chemistry Tryptophan Tryptophan degradation Tryptophan Oxygenase Bioavailability Kinetics Biochemistry Drug development Cell culture Drug Design Molecular Medicine |
| Zdroj: | Journal of Medicinal Chemistry. 54(15):5320-5334 |
| ISSN: | 0022-2623 |
| DOI: | 10.1021/jm2006782 |
| Popis: | Tryptophan catabolism mediated by indoleamine 2,3-dioxygenase (IDO) is an important mechanism of peripheral immune tolerance contributing to tumoral immune resistance. IDO inhibition is thus an active area of research in drug development. Recently, our group has shown that tryptophan 2,3-dioxygenase (TDO), an unrelated hepatic enzyme also catalyzing the first step of tryptophan degradation, is also expressed in many tumors and that this expression prevents tumor rejection by locally depleting tryptophan. Herein, we report a structure-activity study on a series of 3-(2-(pyridyl)ethenyl)indoles. More than 70 novel derivatives were synthesized, and their TDO inhibitory potency was evaluated. The rationalization of the structure-activity relationships (SARs) revealed essential features to attain high TDO inhibition and notably a dense H-bond network mainly involving His(55) and Thr(254) residues. Our study led to the identification of a very promising compound (58) displaying good TDO inhibition (K(i) = 5.5 μM), high selectivity, and good oral bioavailability. Indeed, 58 was chosen for preclinical evaluation. |
| Databáze: | OpenAIRE |
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