Abstract
Design approaches for inhibitors of protein-protein interactions are rare, but highly sought after.
Here, we report that O-phosphorylation of simple derivatives of the natural products
dihydrocapsaicin and N-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 (Ki
= 0.34
µM), whilst displaying 35-fold selectivity over the highly homologous STAT5a (Ki
= 13.0 µM). 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 O-phosphorylation of appropriately preselected
natural products or natural product derivatives as a semi-rational design approach for small
molecules that selectively inhibit phosphorylation-dependent protein-protein interaction domains
in cultured human tumor cells.
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