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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.

Original publication

DOI

10.1021/acs.jmedchem.1c00323

Type

Journal article

Journal

Journal of medicinal chemistry

Publication Date

02/08/2021

Volume

64

Pages

10967 - 10980

Addresses

Louvain Drug Research Institute (LDRI), Université Catholique de Louvain (UCLouvain), Brussels B-1200, Belgium.