Boronic Acid: A Novel Pharmacophore Targeting Src Homology 2 (SH2) Domain of STAT3

SH2 domains have been recognized as promising targets
for various
human diseases. However, targeting SH2 domains with phosphopeptides
or small-molecule inhibitors derived from bioisosteres of the phosphate
group is still challenging. Identifying novel bioisosteres of the
phosphate group to achieve favorable in vivo potency
is urgently needed. Here, we report the feasibility of targeting the
STAT3-SH2 domain with a boronic acid group and the identification
of a highly potent inhibitor compound 7 by replacing
the carboxylic acid of compound 4 with a boronic acid.
Compound 7 shows higher binding affinity, better cellular
potency, more favorable PK profiles, and higher in vivo antitumor activity than 4. The stronger anticancer
effect of 7 partially stems from its covalent binding
mode with the SH2 domain, verified by the washout experiments. The
relatively high level of sequence conservation among SH2 domains makes
the results presented here of general significance.