Phosphorylation of Capsaicinoid Derivatives Provides Highly Potent and Selective Inhibitors of the Transcription Factor STAT5b
Citations Over TimeTop 18% of 2015 papers
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), 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.
Related Papers
- → Connexin 43-serine 282 modulates serine 279 phosphorylation in cardiomyocytes(2019)14 cited
- → Systems analysis of phosphorylation‐regulated Bcl‐2 interactions establishes a model to reconcile the controversy over the significance of Bcl‐2 phosphorylation(2018)13 cited
- → Two phosphorylation sites on eIF‐2α(1990)12 cited
- The Effect of O-GlcNAcylation on Phosphorylation of tau(2003)
- → Tropomyosin Phosphorylation in Healthy and Diseased Hearts(2010)