β-lapachone is a naturally occurring 1,2-naphthoquinone-based compound that has been advanced into clinical trials based on its tumor-selective cytotoxic properties. Previously, we focused on the related 1,4-naphthoquinone pharmacophore as a basic core structure for developing a series of potent indoleamine 2,3-dioxygenase 1 (IDO1) enzyme inhibitors. In this study, we identified IDO1 inhibitory activity as a previously unrecognized attribute of the clinical candidate β-lapachone. Enzyme kinetics-based analysis of β-lapachone indicated an uncompetitive mode of inhibition, while computational modeling predicted binding within the IDO1 active site consistent with other naphthoquinone derivatives. Inhibition of IDO1 has previously been shown to breach the pathogenic tolerization that constrains the immune system from being able to mount an effective anti-tumor response. Thus, the finding that β-lapachone has IDO1 inhibitory activity adds a new dimension to its potential utility as an anti-cancer agent distinct from its cytotoxic properties, and suggests that a synergistic benefit can be achieved from its combined cytotoxic and immunologic effects.
PDF (876.46 KB PDF FORMAT)
RIS citation (ENDNOTE, REFERENCE MANAGER, PROCITE, REFWORKS)
BibTex citation (BIBDESK, LATEX)
My experience with Int J Tryptophan Research has been excellent. The editors and reviewers were most helpful and very "open" intellectually given we were proposing a novel and counter-intuitive hypothesis. The administrative staff have been patient, quick, helpful and friendly. I would and have recommended this group of journals to colleagues.
All authors are surveyed after their articles are published. Authors are asked to rate their experience in a variety of areas, and their responses help us to monitor our performance. Presented here are their responses in some key areas. No 'poor' or 'very poor' responses were received; these are represented in the 'other' category.See Our Results
Copyright © 2014 Libertas Academica Ltd (except open access articles and accompanying metadata and supplementary files.)