Exploiting
an Allosteric Binding Site of PRMT3 Yields
Potent and Selective Inhibitors
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Abstract
Protein arginine
methyltransferases (PRMTs) play an important role
in diverse biological processes. Among the nine known human PRMTs,
PRMT3 has been implicated in ribosomal biosynthesis via asymmetric
dimethylation of the 40S ribosomal protein S2 and in cancer via interaction
with the DAL-1 tumor suppressor protein. However, few selective inhibitors
of PRMTs have been discovered. We recently disclosed the first selective
PRMT3 inhibitor, which occupies a novel allosteric binding site and
is noncompetitive with both the peptide substrate and cofactor. Here
we report comprehensive structure–activity relationship studies
of this series, which resulted in the discovery of multiple PRMT3
inhibitors with submicromolar potencies. An X-ray crystal structure
of compound <b>14u</b> in complex with PRMT3 confirmed that
this inhibitor occupied the same allosteric binding site as our initial
lead compound. These studies provide the first experimental evidence
that potent and selective inhibitors can be created by exploiting
the allosteric binding site of PRMT3