Abstract
The molecular determinants
for the activities of the reported benzoic
acid (SH4–54), salicylic acid (BP-1–102), and benzohydroxamic
acid (SH5–07)-based STAT3 inhibitors were investigated to design
optimized analogues. All three leads are based on an
N
-methylglycinamide scaffold, with its two amine groups condensed
with three different functionalities. The three functionalities and
the CH
2
group of the glycinamide scaffold were separately
modified. The replacement of the pentafluorobenzene or cyclohexylbenzene,
or replacing the benzene ring of the aromatic carboxylic or hydroxamic
acid motif with heterocyclic components (containing nitrogen and oxygen
elements) all decreased potency. Notably, the Ala-linker analogues,
1a
and
2v
, and the Pro-based derivative
5d
, all with (
R
)-configuration at the chiral
center, had improved inhibitory activity and selectivity against STAT3
DNA-binding activity
in vitro
, with IC
50
of 3.0 ± 0.9, 1.80 ± 0.94, and 2.4 ± 0.2 μM,
respectively. Compounds
1a
,
2v
,
5d
, and other analogues inhibited constitutive STAT3 phosphorylation
and activation in human breast cancer and melanoma lines, and blocked
tumor cell viability, growth, colony formation, and migration
in vitro
. Pro-based analogue,
5h
, with a relatively
polar tetrahydropyranyl (THP) ring, instead of the cyclohexyl, showed
improved permeability. In general, the (
R
)-configuration
Pro-based analogs showed the overall best profile, including physicochemical
properties (e.g., microsomal metabolic stability, Caco-2 permeability),
and in particular,
5d
showed improved tumor-cell specificity.