Rational design of original fused-cycle selective inhibitors of tryptophan 2,3-dioxygenase

Rational design of original fused-cycle selective inhibitors of tryptophan 2,3-dioxygenase

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-...

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Bibliographic Details
Main Authors: Kozlova, A, Thabault, L, Liberelle, M, Klaessens, S, Prévost, JRC, Mathieu, C, Pilotte, L, Stroobant, V, Van den Eynde, B, Frédérick, R
Format: Journal article
Language:English
Published: American Chemical Society 2021
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Summary: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.

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