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J Med Chem. 2016 Nov 10;59(21):9881-9889. Epub 2016 Nov 2.

Structure-Based Design of a Covalent Inhibitor of the SET Domain-Containing Protein 8 (SETD8) Lysine Methyltransferase.

Author information

1
Department of Pharmacological Sciences and Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai , New York, New York 10029, United States.
2
Structural Genomics Consortium, University of Toronto , Toronto, Ontario M5G 1L7, Canada.
3
Molecular Pharmacology and Chemistry Program, Memorial Sloan Kettering Cancer Center , New York, New York 10065, United States.
4
Department of Pharmacology and Toxicology, University of Toronto , Toronto, Ontario M5S 1A8, Canada.

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.

PMID:
27804297
PMCID:
PMC5148670
DOI:
10.1021/acs.jmedchem.6b01244
[Indexed for MEDLINE]
Free PMC Article

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