Abstract

The fat mass and obesity associated protein (FTO) is a member of 2-oxoglutarate (2OG) and ferrous iron-dependent nucleic acid oxygenase family. It catalyzes the nucleic acid oxidative demethylation, notably, N6-methyladenosin (m6A) demethylation1. FTO has been reported that plays a role in m6A regulation and associates with cancers, like Acute Myeloid Leukemia (AML)2. Although the mechanism of how m6A regulation causes disease remains uncertain, a selective and potent FTO inhibitor is needed for structural studies and exploring its potential for anti-cancer therapy. By studying crystal structures of FTO in complex with 2OG and substrate mimics, we designed and synthesized two series of FTO inhibitors. We characterized these inhibitors through turnover and binding assays and X-ray crystallography with FTO and the related bacterial enzyme AlkB, and successfully identified a potent inhibitor that employs binding interactions spanning the FTO 2OG and substrate binding sites. Here, we demonstrate the inhibitor’s selectivity to FTO over other clinically targeted 2OG oxygenases and elucidate how structure-based design can be incorporated for identifying potent and selective 2OG oxygenase inhibitors.

Reference:

1. G. Jia, Y. Fu, X. Zhao, Q. Dai, G. Zheng, Y. Yang, C. Yi, T. Lindahl, T. Pan, Y. G. Yang and C. He, Nat Chem Biol, 2011, 7, 885-887.
2. Y. Huang, R. Su, Y. Sheng, L. Dong, Z. Dong, H. Xu, T. Ni, Z. S. Zhang, T. Zhang, C. Li, L. Han, Z. Zhu, F. Lian, J. Wei, Q. Deng, Y. Wang, M. Wunderlich, Z. Gao, G. Pan, D. Zhong, H. Zhou, N. Zhang, J. Gan, H. Jiang, J. C. Mulloy, Z. Qian, J. Chen and C. G. Yang, Cancer Cell, 2019, 35, 677-691 e610.