dc.contributor.author |
Sari, Suat |
en |
dc.contributor.author |
Tomek, Petr |
en |
dc.contributor.author |
Leung, Yee Fun |
en |
dc.contributor.author |
Reynisson, Johannes |
en |
dc.date.accessioned |
2020-01-12T22:19:58Z |
en |
dc.date.issued |
2019-11-28 |
en |
dc.identifier.citation |
Molecules (Basel, Switzerland) 24(23) 28 Nov 2019 |
en |
dc.identifier.issn |
1420-3049 |
en |
dc.identifier.uri |
http://hdl.handle.net/2292/49522 |
en |
dc.description.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. |
en |
dc.format.medium |
Electronic |
en |
dc.language |
eng |
en |
dc.relation.ispartofseries |
Molecules (Basel, Switzerland) |
en |
dc.rights |
Items in ResearchSpace are protected by copyright, with all rights reserved, unless otherwise indicated. Previously published items are made available in accordance with the copyright policy of the publisher. |
en |
dc.rights.uri |
https://researchspace.auckland.ac.nz/docs/uoa-docs/rights.htm |
en |
dc.rights.uri |
https://creativecommons.org/licenses/by/4.0/ |
en |
dc.subject |
Humans |
en |
dc.subject |
Tryptophan Oxygenase |
en |
dc.subject |
Antineoplastic Agents |
en |
dc.subject |
Enzyme Inhibitors |
en |
dc.subject |
Ligands |
en |
dc.subject |
Molecular Structure |
en |
dc.subject |
Structure-Activity Relationship |
en |
dc.subject |
Models, Molecular |
en |
dc.subject |
Indoleamine-Pyrrole 2,3,-Dioxygenase |
en |
dc.subject |
Drug Discovery |
en |
dc.subject |
Drug Development |
en |
dc.title |
Discovery and Characterisation of Dual Inhibitors of Tryptophan 2,3-Dioxygenase (TDO2) and Indoleamine 2,3-Dioxygenase 1 (IDO1) Using Virtual Screening. |
en |
dc.type |
Journal Article |
en |
dc.identifier.doi |
10.3390/molecules24234346 |
en |
pubs.issue |
23 |
en |
pubs.volume |
24 |
en |
dc.rights.holder |
Copyright: The authors |
en |
pubs.publication-status |
Published |
en |
dc.rights.accessrights |
http://purl.org/eprint/accessRights/OpenAccess |
en |
pubs.subtype |
research-article |
en |
pubs.subtype |
Journal Article |
en |
pubs.elements-id |
788966 |
en |
pubs.org-id |
Medical and Health Sciences |
en |
pubs.org-id |
Medical Sciences |
en |
pubs.org-id |
Auckland Cancer Research |
en |
pubs.org-id |
Science |
en |
pubs.org-id |
Science Research |
en |
pubs.org-id |
Maurice Wilkins Centre (2010-2014) |
en |
dc.identifier.eissn |
1420-3049 |
en |
pubs.record-created-at-source-date |
2019-12-05 |
en |
pubs.dimensions-id |
31795096 |
en |