Journal article
Structure-Based Design of Selective Fat Mass and Obesity Associated Protein (FTO) Inhibitors
S Shishodia, M Demetriades, D Zhang, NY Tam, P Maheswaran, C Clunie-O'Connor, A Tumber, IKH Leung, YM Ng, TM Leissing, AH El-Sagheer, E Salah, T Brown, WS Aik, MA McDonough, CJ Schofield
Journal of Medicinal Chemistry | Published : 2021
Abstract
FTO catalyzes the Fe(II) and 2-oxoglutarate (2OG)-dependent modification of nucleic acids, including the demethylation of N6-methyladenosine (m6A) in mRNA. FTO is a proposed target for anti-cancer therapy. Using information from crystal structures of FTO in complex with 2OG and substrate mimics, we designed and synthesized two series of FTO inhibitors, which were characterized by turnover and binding assays, and by X-ray crystallography with FTO and the related bacterial enzyme AlkB. A potent inhibitor employing binding interactions spanning the FTO 2OG and substrate binding sites was identified. Selectivity over other clinically targeted 2OG oxygenases was demonstrated, including with respe..
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Awarded by Biotechnology and Biological Sciences Research Council
Funding Acknowledgements
W.S.A. thanks the Research Grants Council of Hong Kong for the Early Career Scheme 2019/20 (ref. no. 22301719) for funding. C.J. S. thanks the Biotechnology and Biological Research Council, the Wellcome Trust, and Cancer Research UK for funding. This research was funded in whole, or in part, by the Wellcome Trust [grant no. 106244/Z/14/Z]. S.S. is funded by the Felix Scholarship. S.S. thanks Dr. Adam Hardy, University of Oxford, for useful scientific discussion. We thank the Diamond Light Source and staff for the allocation of beam time and support. For the purpose of open access, the author has applied a CC BY public copyright license to any Author Accepted Manuscript version arising from this submission.