Sari, S, Tomek, P, Leung, E and Reynisson, J ORCID: https://orcid.org/0000-0003-4174-9512 (2019) Discovery and Characterisation of Dual Inhibitors of Tryptophan 2,3-Dioxygenase (TDO2) and Indoleamine 2,3-Dioxygenase 1 (IDO1) Using Virtual Screening. Molecules, 24 (23).

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Discovery and Characterisation of Dual Inhibitors of Tryptophan 2,3-Dioxygenase (TDO2) and Indoleamine 2,3-Dioxygenase 1 (ID.pdf - Published Version
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Abstract

Cancers express tryptophan catabolising enzymes indoleamine 2,3-dioxygenase 1 (IDO1) and tryptophan 2,3-dioxygenase (TDO2) to produce immunosuppressive tryptophan metabolites that undermine patients' immune systems, leading to poor disease outcomes. Both enzymes are validated targets for cancer immunotherapy but there is a paucity of potent TDO2 and dual IDO1/TDO2 inhibitors. To identify novel dual IDO1/TDO2 scaffolds, 3D shape similarity and pharmacophore in silico screening was conducted using TDO2 as a model for both systems. The obtained hits were tested in cancer cell lines expressing mainly IDO1 (SKOV3-ovarian), predominantly TDO2 (A172-brain), and both IDO1 and TDO2 (BT549-breast). Three virtual screening hits were confirmed as inhibitors (TD12, TD18 and TD34). Dose response experiments showed that TD34 is the most potent inhibitor capable of blocking both IDO1 and TDO2 activity, with the IC50 value for BT549 at 3.42 µM. This work identified new scaffolds able to inhibit both IDO1 and TDO2, thus enriching the collection of dual IDO1/TDO2 inhibitors and providing chemical matter for potential development into future anticancer drugs.

Item Type: Article
Additional Information: This is the final published version of the article (version of record). It first appeared online via MPDI at https://doi.org/10.3390/molecules24234346 - please refer to any applicable terms of use of the publisher.
Uncontrolled Keywords: cancer immunotherapy, chemical space, haem-containing dioxygenases, kynurenine, ligand and pharmacophore-based screening, molecular modelling
Subjects: R Medicine > RC Internal medicine > RC0254 Neoplasms. Tumors. Oncology (including Cancer)
R Medicine > RS Pharmacy and materia medica
Divisions: Faculty of Medicine and Health Sciences > School of Pharmacy and Bioengineering
Related URLs:
Depositing User: Symplectic
Date Deposited: 10 Jan 2020 15:28
Last Modified: 12 Feb 2020 09:52
URI: https://eprints.keele.ac.uk/id/eprint/7487

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