Tryptophan 2,3-dioxygenase (TDO) inhibitors. 3-(2-(pyridyl)ethenyl)indoles as potential anticancer immunomodulators.

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Dolusic E, Larrieu P, Moineaux L, Stroobant V, Pilotte L, Colau D, Pochet L, Van den Eynde B, Masereel B, Wouters J, Frederick R

Tryptophan 2,3-dioxygenase (TDO) inhibitors. 3-(2-(pyridyl)ethenyl)indoles as potential anticancer immunomodulators.

J Med Chem. 2011 Aug 11;54(15):5320-34. doi: 10.1021/jm2006782. Epub 2011 Jul 18.

PubMed ID

21726069 [ View in PubMed

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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 muM), high selectivity, and good oral bioavailability. Indeed, 58 was chosen for preclinical evaluation.

DrugBank Data that Cites this Article

Binding Properties

Drug	Target	Property	Measurement	pH	Temperature (°C)
Atenolol	Beta-1 adrenergic receptor	Ki (nM)	170	N/A	N/A	Details
Harmine	Amine oxidase [flavin-containing] A	Ki (nM)	17	N/A	N/A	Details
Imipramine	Sodium-dependent serotonin transporter	Ki (nM)	0.77	N/A	N/A	Details
Isatin	Amine oxidase [flavin-containing] B	Ki (nM)	33	N/A	N/A	Details
Melatonin	Melatonin receptor type 1A	Ki (nM)	0.37	N/A	N/A	Details
Protriptyline	Sodium-dependent noradrenaline transporter	Ki (nM)	2.3	N/A	N/A	Details