Rational Design of Original Fused-Cycle Selective Inhibitors of Tryptophan 2,3-Dioxygenase. - Université de Lille
Article Dans Une Revue Journal of Medicinal Chemistry Année : 2021

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

A. Kozlova
  • Fonction : Auteur
L. Thabault
  • Fonction : Auteur
S. Klaessens
  • Fonction : Auteur
J. R. C. Prévost
  • Fonction : Auteur
C. Mathieu
  • Fonction : Auteur
L. Pilotte
  • Fonction : Auteur
V. Stroobant
  • Fonction : Auteur
B. van den Eynde
  • Fonction : Auteur
R. Frédérick
  • Fonction : Auteur

Résumé

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.

Dates et versions

hal-04606264 , version 1 (10-06-2024)

Identifiants

Citer

A. Kozlova, L. Thabault, Maxime Liberelle, S. Klaessens, J. R. C. Prévost, et al.. Rational Design of Original Fused-Cycle Selective Inhibitors of Tryptophan 2,3-Dioxygenase.. Journal of Medicinal Chemistry, 2021, Journal of Medicinal Chemistry, 64, pp.10967-10980. ⟨10.1021/acs.jmedchem.1c00323⟩. ⟨hal-04606264⟩

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