Discovery and characterisation of dual inhibitors of tryptophan 2,3-dioxygenase (TDO2) and indoleamine 2,3-dioxygenase 1 (IDO1) using virtual screening Suat Sari 1 , Petr Tomek 2 , Euphemia Leung 2 and Jóhannes Reynisson 3 1 Hacettepe University,Turkey, 2 Auckland Cancer Society Research Centre, University of Auckland, New Zealand, 3 School of Pharmacy and Bioengineering, Keele University, UK 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. 1 Both enzymes are validated targets for cancer immunotherapy however, much in demand dual IDO1/TDO2 inhibitors are in short supply. 2 To identify novel dual IDO1/TDO2 scaffolds, a pharmacophore in silico screen was conducted. 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 ( TD12 , TD18 and TD34) virtual screening hits were confirmed as inhibitors. Dose response experiments showed that TD34 is the most potent inhibitor capable of blocking both IDO1 and TDO2 activity, with the IC 50 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. 3 References 1. Pilotte, P. Larrieu, V. Stroobant, D. Colau, E. Dolušić, R. Frédérick, E. De Plaen, C. Uyttenhove, J. Wouters, B. Masereel, B. J. Van den Eynde Proc. Natl. Acad. Sci. USA 2012, 109 , 2497. 2. Yang, S. Zhang, X. Fang, L. Guo, N. Hu, Z. Guo, X. Li, S. Yang, J. C. He, C. Kuang, Q. Yang, J. Med. Chem. 2019, 62 , 9161. 3. Sari, P. Tomek, E. Leung, J. Reynisson, Molecules , 2019, 24 , 4346.
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