Stafia-1: a STAT5a-Selective Inhibitor Developed via Docking-Based Screening of in Silico O-Phosphorylated Fragments |
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Authors: | Dr Kalaiselvi Natarajan Daniel Müller-Klieser Stefan Rubner Prof?Dr Thorsten Berg |
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Institution: | 1. Institute of Organic Chemistry, Leipzig University, Johannisallee 29, 04103 Leipzig, Germany;2. Institute of Organic Chemistry, Leipzig University, Johannisallee 29, 04103 Leipzig, Germany
These authors contributed equally to this work. |
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Abstract: | We present a new approach for the identification of inhibitors of phosphorylation-dependent protein–protein interaction domains, in which phenolic fragments are adapted by in silico O-phosphorylation before docking-based screening. From a database of 10 369 180 compounds, we identified 85 021 natural product-derived phenolic fragments, which were virtually O-phosphorylated and screened for in silico binding to the STAT3 SH2 domain. Nine screening hits were then synthesized, eight of which showed a degree of in vitro inhibition of STAT3. After analysis of its selectivity profile, the most potent inhibitor was then developed to Stafia-1, the first small molecule shown to preferentially inhibit the STAT family member STAT5a over the close homologue STAT5b. A phosphonate prodrug based on Stafia-1 inhibited STAT5a with selectivity over STAT5b in human leukemia cells, providing the first demonstration of selective in vitro and intracellular inhibition of STAT5a by a small-molecule inhibitor. |
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