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-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.