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

Kyle V. Butler, Anqi Ma, Wenyu Yu, Fengling Li, Wolfram Tempel, Nicolas Babault, Fabio Pittella-Silva, Jason Shao, Junyi Wang, Minkui Luo, Masoud Vedadi, Peter J. Brown, Cheryl H. Arrowsmith, Jian Jin

Research output: Contribution to journalArticlepeer-review

25 Scopus citations

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.

Original languageEnglish
Pages (from-to)9881-9889
Number of pages9
JournalJournal of Medicinal Chemistry
Volume59
Issue number21
DOIs
StatePublished - 10 Nov 2016

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