Antitumour agents as inhibitors of tryptophan 2,3-dioxygenase

•∼2800 National Cancer Institute USA compounds have been screened as potential inhibitors of TDO and/or IDO.•Seven compounds with anti-tumour properties have been identified as potent inhibitors.•NSC 36398 (taxifolin, dihydroquercetin) is selective for TDO with a Ki of 16M.•This may help further our understanding of the role of TDO in cancer. The involvement of tryptophan 2,3-dioxygenase (TDO) in cancer biology has recently been described, with the enzyme playing an immunomodulatory role, suppressing antitumour immune responses and promoting tumour cell survival and proliferation. This finding reinforces the need for specific inhibitors of TDO that may potentially be developed for therapeutic use. In this work we have screened ∼2800 compounds from the library of the National Cancer Institute USA and identified seven potent inhibitors of TDO with inhibition constants in the nanomolar or low micromolar range. All seven have antitumour properties, killing various cancer cell lines. For comparison, the inhibition potencies of these compounds were tested against IDO and their inhibition constants are reported. Interestingly, this work reveals that NSC 36398 (dihydroquercetin, taxifolin), with an in vitro inhibition constant of ∼16μM, is the first TDO-selective inhibitor reported.