Selective, Small-Molecule Co-Factor Binding Site Inhibition of a Su(var)3–9, Enhancer of Zeste, Trithorax Domain Containing Lysine Methyltransferase

The
first chemical probe to primarily occupy the co-factor binding
site of a Su­(var)­3−9, enhancer of a zeste, trithorax (SET)
domain containing protein lysine methyltransferase (PKMT) is reported.
Protein methyltransferases require S-adenosylmethionine
(SAM) as a co-factor (methyl donor) for enzymatic activity. However,
SAM itself represents a poor medicinal chemistry starting point for
a selective, cell-active inhibitor given its extreme physicochemical
properties and its role in multiple cellular processes. A previously
untested medicinal chemistry strategy of deliberate file enrichment
around molecules bearing the hallmarks of SAM, but with improved lead-like
properties from the outset, yielded viable hits against SET and MYND
domain-containing protein 2 (SMYD2) that were shown to bind in the
co-factor site. These leads were optimized to identify a highly biochemically
potent, PKMT-selective, and cell-active chemical probe. While substrate-based
inhibitors of PKMTs are known, this represents a novel, co-factor-derived
strategy for the inhibition of SMYD2 which may also prove applicable
to lysine methyltransferase family members previously thought of as
intractable.