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

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

doi:10.1021/acs.jmedchem.6b01244

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

Journal Article · Wed Nov 02 00:00:00 EDT 2016 · Journal of Medicinal Chemistry

DOI:https://doi.org/10.1021/acs.jmedchem.6b01244· OSTI ID:1352275

Butler, Kyle V. ^[1]; Ma, Anqi ^[1]; Yu, Wenyu ^[2]; Li, Fengling ^[2]; Tempel, Wolfram ^[2]; Babault, Nicolas ^[1]; Pittella-Silva, Fabio ^[3]; Shao, Jason ^[1]; Wang, Junyi ^[3]; Luo, Minkui ^[3]; Vedadi, Masoud ^[2]; Brown, Peter J. ^[2]; Arrowsmith, Cheryl H. ^[2]; Jin, Jian ^[1]

Icahn School of Medicine at Mount Sinai, New York, NY (United States)
Univ. of Toronto, ON (Canada)
Memorial Sloan Kettering Cancer Center, New York, NY (United States)

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. In conclusiont, this work provides atomic-level perspective on the inhibition of SETD8 by small molecules and will help identify high-quality chemical probes of SETD8.

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Research Organization:: Argonne National Laboratory (ANL), Argonne, IL (United States). Advanced Photon Source (APS)

Sponsoring Organization:: National Institutes of Health (NIH); AbbVie; Bayer Pharma AG; Boehringer Ingelheim; Canada Foundation for Innovation; Eshelman Institute for Innovation; Genome Canada; Innovative Medicines Initiative; Janssen; Merck & Co.; Novartis Pharma AG; Ontario Ministry of Economic Development and Innovation; Pfizer; São Paulo Research Foundation (FAPESP); Takeda; Wellcome Trust; American Cancer Society; USDOE Office of Science (SC), Biological and Environmental Research (BER)

Grant/Contract Number:: R01GM103893; 115766; AC02-06CH11357

OSTI ID:: 1352275

Journal Information:: Journal of Medicinal Chemistry, Vol. 59, Issue 21; ISSN 0022-2623

Publisher:: American Chemical Society (ACS)Copyright Statement

Country of Publication:: United States

Language:: ENGLISH

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Cited by: 28 works

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

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