Structure-Based Design of Selective Fat Mass and Obesity Associated Protein (FTO) Inhibitors

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 - 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 - https://www.scopus.com/pages/publications/85119435189

U2 - 10.1021/acs.jmedchem.1c01204

DO - 10.1021/acs.jmedchem.1c01204

M3 - 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 -