Structure-Based Design of a Covalent Inhibitor of the SET Domain-Containing Protein 8 (SETD8) Lysine Methyltransferase.
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 IC50value 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.
Department of Pharmacological Sciences and Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai , New York, New York 10029, United States.
Kyle V
KV
Butler
Department of Pharmacological Sciences and Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai , New York, New York 10029, United States.
Anqi
A
Ma
Structural Genomics Consortium, University of Toronto , Toronto, Ontario M5G 1L7, Canada.
Wenyu
W
Yu
Structural Genomics Consortium, University of Toronto , Toronto, Ontario M5G 1L7, Canada.
Fengling
F
Li
Structural Genomics Consortium, University of Toronto , Toronto, Ontario M5G 1L7, Canada.
Wolfram
W
Tempel
Department of Pharmacological Sciences and Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai , New York, New York 10029, United States.
Nicolas
N
Babault
Molecular Pharmacology and Chemistry Program, Memorial Sloan Kettering Cancer Center , New York, New York 10065, United States.
Fabio
F
Pittella-Silva
Department of Pharmacological Sciences and Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai , New York, New York 10029, United States.
Jason
J
Shao
Molecular Pharmacology and Chemistry Program, Memorial Sloan Kettering Cancer Center , New York, New York 10065, United States.
Junyi
J
Wang
Molecular Pharmacology and Chemistry Program, Memorial Sloan Kettering Cancer Center , New York, New York 10065, United States.
Minkui
M
Luo
Structural Genomics Consortium, University of Toronto , Toronto, Ontario M5G 1L7, Canada.|Department of Pharmacology and Toxicology, University of Toronto , Toronto, Ontario M5S 1A8, Canada.
Masoud
M
Vedadi
Structural Genomics Consortium, University of Toronto , Toronto, Ontario M5G 1L7, Canada.
Peter J
PJ
Brown
Structural Genomics Consortium, University of Toronto , Toronto, Ontario M5G 1L7, Canada.|Department of Pharmacology and Toxicology, University of Toronto , Toronto, Ontario M5S 1A8, Canada.
Cheryl H
CH
Arrowsmith
Department of Pharmacological Sciences and Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai , New York, New York 10029, United States.
Jian
J
Jin
D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D011495:Histone-Lysine N-Methyltransferase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D008958:Models, Molecular; D015394:Molecular Structure; D013329:Structure-Activity Relationship
D004791:Enzyme Inhibitors; D011495:Histone-Lysine N-Methyltransferase; C470730:KMT5A protein, human