title: Tryptophan 2,3-dioxygenase (TDO) inhibitors. 3-(2-(pyridyl)ethenyl)indoles as potential anticancer immunomodulators.
abstract: 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.
authors: Drug Design and Discovery Center, University of Namur, Namur, Belgium.
authors: Eduard
authors: E
authors: Dolusić
authors: Pierre
authors: P
authors: Larrieu
authors: Laurence
authors: L
authors: Moineaux
authors: Vincent
authors: V
authors: Stroobant
authors: Luc
authors: L
authors: Pilotte
authors: Didier
authors: D
authors: Colau
authors: Lionel
authors: L
authors: Pochet
authors: Benoît
authors: B
authors: Van den Eynde
authors: Bernard
authors: B
authors: Masereel
authors: Johan
authors: J
authors: Wouters
authors: Raphaël
authors: R
authors: Frédérick
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000494:pharmacology* / Q000627:therapeutic use; D001682:Biological Availability; D002460:Cell Line; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000627:therapeutic use*; D006801:Humans; D007155:Immunologic Factors / Q000494:pharmacology*; D007211:Indoles / Q000138:chemical synthesis / Q000494:pharmacology* / Q000627:therapeutic use; D007700:Kinetics; D051379:Mice; D009369:Neoplasms / Q000201:enzymology; D013329:Structure-Activity Relationship; D014366:Tryptophan Oxygenase / Q000037:antagonists & inhibitors*
chemical_list: D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D007155:Immunologic Factors; D007211:Indoles; D014366:Tryptophan Oxygenase