Rational Design of Original Fused-Cycle Selective Inhibitors of Tryptophan 2,3-Dioxygenase

Kozlova, Arina;Thabault, Léopold;Liberelle, Maxime;Klaessens, Simon;Frédérick, Raphaël;et.al.
(2021) Journal of Medicinal Chemistry — (2021)

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Abstract
(en) 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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Kozlova, A., Thabault, L., Liberelle, M., Klaessens, S., Prévost, J. R. C., Mathieu, C., Pilotte, L., Stroobant, V., Van den Eynde, B., & Frédérick, R. (2021). Rational Design of Original Fused-Cycle Selective Inhibitors of Tryptophan 2,3-Dioxygenase. Journal of Medicinal Chemistry. Accepted/in-press. https://doi.org/10.1021/acs.jmedchem.1c00323 (Original work published 2021)