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Biochem Biophys Res Commun. 2014 Jan 3;443(1):28-31. doi: 10.1016/j.bbrc.2013.11.037. Epub 2013 Nov 19.

Antitumour agents as inhibitors of tryptophan 2,3-dioxygenase.

Author information

1
EaStCHEM School of Chemistry, University of Edinburgh, West Mains Road, Edinburgh EH9 3JJ, UK.
2
EaStCHEM School of Chemistry, University of Edinburgh, West Mains Road, Edinburgh EH9 3JJ, UK. Electronic address: C.G.Mowat@ed.ac.uk.

Abstract

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 ~16 μM, is the first TDO-selective inhibitor reported.

KEYWORDS:

Cancer; IDO; KMO; Kynurenine pathway; NCI; National Cancer Institute USA; TDO; Tryptophan 2,3-dioxygenase; human indoleamine 2,3-dioxygenase; human tryptophan 2,3-dioxygenase; kynurenine 3-monoxygenase

PMID:
24269239
DOI:
10.1016/j.bbrc.2013.11.037
[Indexed for MEDLINE]

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