Structure-based design of selective fat mass and obesity associated protein (FTO) Inhibitors
Structure-based design of selective fat mass and obesity associated protein (FTO) Inhibitors
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.
16609–16625
Shishodia, Shifali
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Demetriades, Marina
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Zhang, Dong
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Tam, Nok Yin
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Maheswaran, Pratheesh
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Clunie-O’Connor, Caitlin
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Tumber, Anthony
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Leung, Ivanhoe K.H.
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Ng, Yi Min
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Leissing, Thomas M.
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El-Sagheer, Afaf
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Salah, Eidarus
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Brown, Tom
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Aik, Wei Shen
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McDonough, Michael A
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Schofield, Christopher J.
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25 November 2021
Shishodia, Shifali
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Demetriades, Marina
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Zhang, Dong
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Tam, Nok Yin
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Maheswaran, Pratheesh
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Clunie-O’Connor, Caitlin
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Tumber, Anthony
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Leung, Ivanhoe K.H.
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Ng, Yi Min
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Leissing, Thomas M.
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El-Sagheer, Afaf
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Salah, Eidarus
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Brown, Tom
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Aik, Wei Shen
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McDonough, Michael A
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Schofield, Christopher J.
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Shishodia, Shifali, Demetriades, Marina, Zhang, Dong, Tam, Nok Yin, Maheswaran, Pratheesh, Clunie-O’Connor, Caitlin, Tumber, Anthony, Leung, Ivanhoe K.H., Ng, Yi Min, Leissing, Thomas M., El-Sagheer, Afaf, Salah, Eidarus, Brown, Tom, Aik, Wei Shen, McDonough, Michael A and Schofield, Christopher J.
(2021)
Structure-based design of selective fat mass and obesity associated protein (FTO) Inhibitors.
Journal of Medicinal Chemistry, 64 (22), .
(doi:10.1021/acs.jmedchem.1c01204).
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 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.
Text
acs.jmedchem.1c01204
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Accepted/In Press date: 11 November 2021
e-pub ahead of print date: 11 November 2021
Published date: 25 November 2021
Identifiers
Local EPrints ID: 477942
URI: http://eprints.soton.ac.uk/id/eprint/477942
ISSN: 0022-2623
PURE UUID: 956528ee-829b-47ff-9403-46a4d93f0233
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Date deposited: 16 Jun 2023 16:48
Last modified: 17 Mar 2024 03:04
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Contributors
Author:
Shifali Shishodia
Author:
Marina Demetriades
Author:
Dong Zhang
Author:
Nok Yin Tam
Author:
Pratheesh Maheswaran
Author:
Caitlin Clunie-O’Connor
Author:
Anthony Tumber
Author:
Ivanhoe K.H. Leung
Author:
Yi Min Ng
Author:
Thomas M. Leissing
Author:
Afaf El-Sagheer
Author:
Eidarus Salah
Author:
Wei Shen Aik
Author:
Michael A McDonough
Author:
Christopher J. Schofield
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