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 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.