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)