Lotz-Jenne, C.; Lange, R.; Cren, S.; Bourquin, G.; Goglia, L.; Kimmerlin, T.; Wicki, M.; Mueller, M.; Artico, N.; Ackerknecht, S.; Joesch, C.; Mac Sweeney, A.

Tryptophan-2,3-dioxygenase (TDO2) and indoleamine-2,3-dioxygenase (IDO1) catalyze the conversion of L-tryptophan to N-formyl-kynurenine and play important roles in metabolism, inflammation, and tumor immune surveillance. Their enzymatic activities depend on their heme contents, which vary dynamically according to biological conditions. Inhibitors binding to heme-containing holo-TDO2 are known, but to date no inhibitor that binds to the heme-free state (apo-TDO2) has been reported. We describe the discovery and co-crystal structure of a first apo-TDO2 targeting inhibitor, to our knowledge, which inhibits cellular TDO2 activity at micromolar concentrations.