TY - JOUR
T1 - Structure-Based Design of Selective Fat Mass and Obesity Associated Protein (FTO) Inhibitors
AU - Shishodia, Shifali
AU - Demetriades, Marina
AU - Zhang, Dong
AU - Tam, Nok Yin
AU - Maheswaran, Pratheesh
AU - Clunie-O'Connor, Caitlin
AU - Tumber, Anthony
AU - Leung, Ivanhoe K.H.
AU - Ng, Yi Min
AU - Leissing, Thomas M.
AU - El-Sagheer, Afaf H.
AU - Salah, Eidarus
AU - Brown, Tom
AU - Aik, Wei Shen
AU - McDonough, Michael A.
AU - Schofield, Christopher J.
N1 - Funding Information:
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.
Publisher Copyright:
© 2021 The Authors. Published by American Chemical Society.
PY - 2021/11/25
Y1 - 2021/11/25
N2 - 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 respect to the hypoxia-inducible factor prolyl and asparaginyl hydroxylases (PHD2 and FIH) and selected JmjC histone demethylases (KDMs). The results illustrate how structure-based design can enable the identification of potent and selective 2OG oxygenase inhibitors and will be useful for the development of FTO inhibitors for use in vivo.
AB - 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 respect to the hypoxia-inducible factor prolyl and asparaginyl hydroxylases (PHD2 and FIH) and selected JmjC histone demethylases (KDMs). The results illustrate how structure-based design can enable the identification of potent and selective 2OG oxygenase inhibitors and will be useful for the development of FTO inhibitors for use in vivo.
UR - http://www.scopus.com/inward/record.url?scp=85119435189&partnerID=8YFLogxK
U2 - 10.1021/acs.jmedchem.1c01204
DO - 10.1021/acs.jmedchem.1c01204
M3 - Journal article
C2 - 34762429
AN - SCOPUS:85119435189
SN - 0022-2623
VL - 64
SP - 16609
EP - 16625
JO - Journal of Medicinal Chemistry
JF - Journal of Medicinal Chemistry
IS - 22
ER -