Título :	Structure-based design of a covalent Inhibitor of the SET domain-containing protein 8 (SETD8) lysine methyltransferase
Autor :	Butler, Kyle V. Anqi Ma Wenyu Yu Fengling Li Tempel, Wolfram Babault, Nicolas Pittella-Silva, Fabio Shao, Jason Junyi Wang Minkui Luo Vedadi, Masoud Brown, Peter J. Arrowsmith, Cheryl H. Jian Jin
metadata.dc.contributor.affiliation:	Department of Pharmacological Sciences and Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, New York 10029, Estados Unidos Structural Genomics Consortium, Universidade de Toronto, Toronto, Ontário M5G 1L7, Canadá Molecular Pharmacology and Chemistry Program, Memorial Sloan Kettering Cancer Center, New York, New York 10065, Estados Unidos Department of Pharmacology and Toxicology, University of Toronto, Toronto, Ontário M5S 1A8, Canadá
Assunto::	Adutos Estrutura cristalina Inibidores Monômeros Peptídeos Proteínas
Fecha de publicación :	2016
Editorial :	American Chemical Society
Citación :	BUTLER, Kyle V. et al. Structure-based design of a covalent Inhibitor of the SET domain-containing protein 8 (SETD8) lysine methyltransferase. Journal of Medicinal Chemistry, v. 59, 21, p. 9881–9889, 2016. DOI: https://doi.org/10.1021/acs.jmedchem.6b01244.
Abstract:	Selective inhibitors of protein lysine methyltransferases, including SET domain-containing protein 8 (SETD8), are highly desired, as only a fraction of these enzymes are associated with high-quality inhibitors. From our previously discovered SETD8 inhibitor, we developed a more potent analog and solved a cocrystal structure, which is the first crystal structure of SETD8 in complex with a small-molecule inhibitor. This cocrystal structure allowed the design of a covalent inhibitor of SETD8 (MS453), which specifically modifies a cysteine residue near the inhibitor binding site, has an IC50 value of 804 nM, reacts with SETD8 with near-quantitative yield, and is selective for SETD8 against 28 other methyltransferases. We also solved the crystal structure of the covalent inhibitor in complex with SETD8. This work provides atomic-level perspective on the inhibition of SETD8 by small molecules and will help identify high-quality chemical probes of SETD8.
DOI:	https://doi.org/10.1021/acs.jmedchem.6b01244
metadata.dc.relation.publisherversion:	https://pubs.acs.org/doi/10.1021/acs.jmedchem.6b01244#
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