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), while 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 semirational design approach for small molecules that selectively inhibit phosphorylation-dependent protein-protein interaction domains in cultured human tumor cells.