Structure-based design of a covalent inhibitor of the SET domain-containing protein 8 (SETD8) lysine methyltransferase Journal Article
| Authors: | Butler, K. V.; Ma, A.; Yu, W.; Li, F.; Tempel, W.; Babault, N.; Pittella-Silva, F.; Shao, J.; Wang, J.; Luo, M.; Vedadi, M.; Brown, P. J.; Arrowsmith, C. H.; Jin, J. |
| Article Title: | Structure-based design of a covalent inhibitor of the SET domain-containing protein 8 (SETD8) lysine methyltransferase |
| 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. © 2016 American Chemical Society. |
| Journal Title: | Journal of Medicinal Chemistry |
| Volume: | 59 |
| Issue: | 21 |
| ISSN: | 0022-2623 |
| Publisher: | American Chemical Society |
| Date Published: | 2016-11-10 |
| Start Page: | 9881 |
| End Page: | 9889 |
| Language: | English |
| DOI: | 10.1021/acs.jmedchem.6b01244 |
| PROVIDER: | scopus |
| PMCID: | PMC5148670 |
| PUBMED: | 27804297 |
| DOI/URL: | |
| Notes: | Article -- Export Date: 6 December 2016 -- Source: Scopus |
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