10.1021/acs.jmedchem.6b01244.s001
Kyle V. Butler
Kyle V.
Butler
Anqi Ma
Anqi
Ma
Wenyu Yu
Wenyu
Yu
Fengling Li
Fengling
Li
Wolfram Tempel
Wolfram
Tempel
Nicolas Babault
Nicolas
Babault
Fabio Pittella-Silva
Fabio
Pittella-Silva
Jason Shao
Jason
Shao
Junyi Wang
Junyi
Wang
Minkui Luo
Minkui
Luo
Masoud Vedadi
Masoud
Vedadi
Peter
J. Brown
Peter
J.
Brown
Cheryl H. Arrowsmith
Cheryl H.
Arrowsmith
Jian Jin
Jian
Jin
Structure-Based
Design of a Covalent Inhibitor of
the SET Domain-Containing Protein 8 (SETD8) Lysine Methyltransferase
American Chemical Society
2016
cocrystal structure
crystal structure
Domain-Containing Protein 8
MS
domain-containing protein 8
inhibitor binding site
SETD 8 inhibitor
SETD 8
protein lysine methyltransferases
IC 50 value
covalent inhibitor
2016-11-02 11:53:25
Journal contribution
https://acs.figshare.com/articles/journal_contribution/Structure-Based_Design_of_a_Covalent_Inhibitor_of_the_SET_Domain-Containing_Protein_8_SETD8_Lysine_Methyltransferase/4185078
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 IC<sub>50</sub> 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.