Journal ArticleDOI
Development of Cell-Active N6-Methyladenosine RNA Demethylase FTO Inhibitor
Baoen Chen,Fei Ye,Lu Yu,Guifang Jia,Xiaotian Huang,X.-B. Zhang,Shuying Peng,Kai Chen,Meining Wang,Shouze Gong,Ruihan Zhang,Jinya Yin,Haiyan Li,Yiming Yang,Hong Liu,Jiwen Zhang,Hai-Yan Zhang,Ao Zhang,Hualiang Jiang,Cheng Luo,Cai-Guang Yang,Cai-Guang Yang +21 more
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TLDR
The first identification of several small-molecule inhibitors of human FTO demethylase is reported, including the most potent compound, the natural product rhein, which is neither a structural mimic of 2-oxoglutarate nor a chelator of metal ion.Abstract:
The direct nucleic acid repair dioxygenase FTO is an enzyme that demethylates N6-methyladenosine (m6A) residues in mRNA in vitro and inside cells. FTO is the first RNA demethylase discovered that also serves a major regulatory function in mammals. Together with structure-based virtual screening and biochemical analyses, we report the first identification of several small-molecule inhibitors of human FTO demethylase. The most potent compound, the natural product rhein, which is neither a structural mimic of 2-oxoglutarate nor a chelator of metal ion, competitively binds to the FTO active site in vitro. Rhein also exhibits good inhibitory activity on m6A demethylation inside cells. These studies shed light on the development of powerful probes and new therapies for use in RNA biology and drug discovery.read more
Citations
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Journal ArticleDOI
The dynamic epitranscriptome: N6-methyladenosine and gene expression control
Kate D. Meyer,Samie R. Jaffrey +1 more
TL;DR: This work has shown that m6A is present in a large subset of the transcriptome in specific regions of mRNA, which suggests that mRNA may undergo post-transcriptional methylation to regulate its fate and function, which is analogous to methyl modifications in DNA.
Journal ArticleDOI
RNA N6-methyladenosine modification in cancers: current status and perspectives
Xiaolan Deng,Xiaolan Deng,Xiaolan Deng,Rui Su,Rui Su,Hengyou Weng,Hengyou Weng,Huilin Huang,Huilin Huang,Zejuan Li,Jianjun Chen,Jianjun Chen +11 more
TL;DR: Recent advances in the study of biological functions and the underlying molecular mechanisms of dysregulated m6A modification and the associated machinery in the pathogenesis and drug response of various types of cancers are focused on.
Journal ArticleDOI
The Critical Role of RNA m6A Methylation in Cancer
TL;DR: Screening for selective and potent RNA methyltransferase, demethylase, or m6A-binding protein inhibitors may lead to compounds suitable for future clinical trials in cancer patients.
Journal ArticleDOI
Small-Molecule Targeting of Oncogenic FTO Demethylase in Acute Myeloid Leukemia.
Yue Huang,Rui Su,Yue Sheng,Lei Dong,Lei Dong,Ze Dong,Hongjiao Xu,Tengfeng Ni,Zijie Scott Zhang,Zhang Tao,Chenying Li,Li Han,Zhen-Yun Zhu,Fulin Lian,Jiangbo Wei,Qiangqiang Deng,Yungui Wang,Mark Wunderlich,Zhiwei Gao,Guoyu Pan,Dafang Zhong,Hu Zhou,Naixia Zhang,Jianhua Gan,Hualiang Jiang,James C. Mulloy,Zhijian Qian,Zhijian Qian,Jianjun Chen,Jianjun Chen,Cai-Guang Yang +30 more
TL;DR: Two promising FTO inhibitors are developed, namely FB23 and FB23-2, which directly bind to FTO and selectively inhibit FTO's m6A demethylase activity, suggesting that FTO is a druggable target and that targeting FTO by small-molecule inhibitors holds potential to treat AML.
Journal ArticleDOI
Meclofenamic acid selectively inhibits FTO demethylation of m6A over ALKBH5
Yue Huang,Jingli Yan,Qi Li,Jiafei Li,Shouzhe Gong,Hu Zhou,Jianhua Gan,Hualiang Jiang,Guifang Jia,Cheng Luo,Cai-Guang Yang +10 more
TL;DR: The collective results highlight the development of functional probes of the FTO enzyme that will enable future biological studies and pave the way for the rational design of potent and specific inhibitors of FTO for use in medicine.
References
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Journal ArticleDOI
A common variant in the FTO gene is associated with body mass index and predisposes to childhood and adult obesity
Timothy M. Frayling,Nicholas J. Timpson,Michael N. Weedon,Eleftheria Zeggini,Eleftheria Zeggini,Eleftheria Zeggini,Rachel M. Freathy,Cecilia M. Lindgren,John R. B. Perry,Katherine S. Elliott,Katherine S. Elliott,Hana Lango,Nigel W. Rayner,Nigel W. Rayner,Nigel W. Rayner,Beverley M. Shields,Lorna W. Harries,Jeffrey C. Barrett,Jeffrey C. Barrett,Sian Ellard,Christopher J. Groves,Christopher J. Groves,Bridget A. Knight,Ann-Marie Patch,Andy R Ness,Shah Ebrahim,Debbie A Lawlor,Susan M. Ring,Yoav Ben-Shlomo,Marjo-Riitta Järvelin,Marjo-Riitta Järvelin,Ulla Sovio,Ulla Sovio,Amanda J. Bennett,Amanda J. Bennett,David Melzer,Luigi Ferrucci,Ruth J. F. Loos,Inês Barroso,Nicholas J. Wareham,Fredrik Karpe,Fredrik Karpe,Katharine R. Owen,Katharine R. Owen,Lon R. Cardon,Mark Walker,Graham A. Hitman,Graham A. Hitman,Colin N. A. Palmer,Colin N. A. Palmer,Alex S. F. Doney,Alex S. F. Doney,Andrew D. Morris,George Davey Smith,Andrew T. Hattersley,Mark I. McCarthy +55 more
TL;DR: A genome-wide search for type 2 diabetes–susceptibility genes identified a common variant in the FTO (fat mass and obesity associated) gene that predisposes to diabetes through an effect on body mass index (BMI).
Journal ArticleDOI
Calculating Structures and Free Energies of Complex Molecules: Combining Molecular Mechanics and Continuum Models
Peter A. Kollman,Irina Massova,Carolina M. Reyes,Bernd Kuhn,Shuanghong Huo,Lillian T. Chong,Matthew Lee,Tai-Sung Lee,Yong Duan,Wei Wang,Oreola Donini,Piotr Cieplak,Jaysharee Srinivasan,David A. Case,Thomas E. Cheatham +14 more
TL;DR: A historical perspective on the application of molecular dynamics to biological macromolecules is presented and recent developments combining state-of-the-art force fields with continuum solvation calculations have allowed for the fourth era of MD applications in which one can often derive both accurate structure and accurate relative free energies from molecular dynamics trajectories.
Journal ArticleDOI
Topology of the human and mouse m6A RNA methylomes revealed by m6A-seq
Dan Dominissini,Sharon Moshitch-Moshkovitz,Schraga Schwartz,Schraga Schwartz,Mali Salmon-Divon,Lior Ungar,Sivan Osenberg,Sivan Osenberg,Karen Cesarkas,Jasmine Jacob-Hirsch,Ninette Amariglio,Martin Kupiec,Rotem Sorek,Gideon Rechavi,Gideon Rechavi +14 more
TL;DR: The findings suggest that RNA decoration by m6A has a fundamental role in regulation of gene expression, and a subset of stimulus-dependent, dynamically modulated sites is identified.
Journal ArticleDOI
Comprehensive Analysis of mRNA Methylation Reveals Enrichment in 3′ UTRs and near Stop Codons
Kate D. Meyer,Yogesh Saletore,Paul Zumbo,Olivier Elemento,Christopher E. Mason,Samie R. Jaffrey +5 more
TL;DR: A method is presented for transcriptome-wide m(6)A localization, which combines m( 6)A-specific methylated RNA immunoprecipitation with next-generation sequencing (MeRIP-Seq) and reveals insights into the epigenetic regulation of the mammalian transcriptome.
Journal ArticleDOI
A genome-wide association study of type 2 diabetes in Finns detects multiple susceptibility variants.
Laura J. Scott,Karen L. Mohlke,Lori L. Bonnycastle,Cristen J. Willer,Yun Li,William L. Duren,Michael R. Erdos,Heather M. Stringham,Peter S. Chines,Anne U. Jackson,Ludmila Prokunina-Olsson,Chia-Jen Ding,Amy J. Swift,Narisu Narisu,Tianle Hu,Randall Pruim,Rui Xiao,Xiao-Yi Li,Karen N. Conneely,Nancy Riebow,Andrew G. Sprau,Maurine Tong,Peggy P. White,Kurt N. Hetrick,Michael W. Barnhart,Craig W. Bark,Janet L. Goldstein,Lee Watkins,Fang Xiang,Jouko Saramies,Thomas A. Buchanan,Richard M. Watanabe,Timo T. Valle,Leena Kinnunen,Gonçalo R. Abecasis,Elizabeth W. Pugh,Kimberly F. Doheny,Richard N. Bergman,Jaakko Tuomilehto,Francis S. Collins,Michael Boehnke +40 more
TL;DR: The number of T2D loci now confidently identified to at least 10 is confirmed, and it is confirmed that variants near TCF7L2, SLC30A8, HHEX, FTO, PPARG, and KCNJ11 are associated with T1D risk.
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Guanqun Zheng,John Arne Dahl,Yamei Niu,Peter Fedorcsak,Chun-Min Huang,Charles J. Li,Cathrine Broberg Vågbø,Yue Shi,Yue Shi,Wen-Ling Wang,Wen-Ling Wang,Shuhui Song,Zhike Lu,Ralph P. G. Bosmans,Qing Dai,Ya-Juan Hao,Ya-Juan Hao,Xin Yang,Xin Yang,Wenming Zhao,Wei-Min Tong,Xiu-Jie Wang,Florian Bogdan,Kari Furu,Ye Fu,Guifang Jia,Xu Zhao,Xu Zhao,Jun Liu,Hans E. Krokan,Arne Klungland,Yun-Gui Yang,Yun-Gui Yang,Chuan He +33 more