Publication
Article Metrics
Citations
Online attention
Structure-based design of selective fat mass and obesity associated protein (FTO) inhibitors
DOI:
10.1021/acs.jmedchem.1c01204
Authors:
Shifali
Shishodia
(University of Oxford)
,
Marina
Demetriades
(University of Oxford)
,
Dong
Zhang
(University of Oxford)
,
Nok Yin
Tam
(Hong Kong Baptist University)
,
Pratheesh
Maheswaran
(University of Oxford)
,
Caitlin
Clunie-O'Connor
(University of Oxford)
,
Anthony
Tumber
(University of Oxford)
,
Ivanhoe K. H.
Leung
(University of Oxford)
,
Yi Min
Ng
(Hong Kong Baptist University)
,
Thomas M.
Leissing
(University of Oxford)
,
Afaf H.
El-Sagheer
(University of Oxford; Suez University)
,
Eidarus
Salah
(University of Oxford)
,
Tom
Brown
(University of Oxford)
,
Wei Shen
Aik
(Hong Kong Baptist University)
,
Michael A.
Mcdonough
(University of Oxford)
,
Christopher J.
Schofield
(University of Oxford)
Co-authored by industrial partner:
No
Type:
Journal Paper
Journal:
Journal Of Medicinal Chemistry
, VOL 276
State:
Published (Approved)
Published:
November 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 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.
Diamond Keywords: Obesity
Subject Areas:
Biology and Bio-materials,
Chemistry,
Medicine
Instruments:
I04-Macromolecular Crystallography
,
I24-Microfocus Macromolecular Crystallography
Added On:
15/11/2021 08:50
Documents:
acs.jmedchem.1c01204.pdf
Discipline Tags:
Non-Communicable Diseases
Health & Wellbeing
Cancer
Biochemistry
Chemistry
Structural biology
Organic Chemistry
Drug Discovery
Life Sciences & Biotech
Technical Tags:
Diffraction
Macromolecular Crystallography (MX)