1 research outputs found
Phosphorylation of Capsaicinoid Derivatives Provides Highly Potent and Selective Inhibitors of the Transcription Factor STAT5b
Design approaches
for inhibitors of proteināprotein interactions
are rare, but highly sought after. Here, we report that <i>O</i>-phosphorylation of simple derivatives of the natural products dihydrocapsaicin
and <i>N</i>-vanillylnonanamide leads to inhibitors of the
SH2 domain of the transcription factor STAT5b. The most potent molecule
is obtained from dihydrocapsaicin in only three synthetic steps. It
has submicromolar affinity for the SH2 domain of STAT5b (<i>K</i><sub>i</sub> = 0.34 Ī¼M), while displaying 35-fold selectivity
over the highly homologous STAT5a (<i>K</i><sub>i</sub> =
13.0 Ī¼M). The corresponding pivaloyloxymethyl ester inhibits
STAT5b with selectivity over STAT5a in human tumor cells. Importantly,
it inhibits cell viability and induces apoptosis in human tumor cells
in a STAT5-dependent manner. Our data validate <i>O</i>-phosphorylation
of appropriately preselected natural products or natural product derivatives
as a semirational design approach for small molecules that selectively
inhibit phosphorylation-dependent proteināprotein interaction
domains in cultured human tumor cells