Signal Transducer and Activator of Transcription 3 (STAT3) plays a significant role in the regulation of important cellular processes. Phosphorylation of Tyr705 and Ser727 activates STAT3 dimerization and translocation to the nucleus. Here, the dimer promotes transcription of targeted genes by binding to specific regions of DNA. In various cancer cell lines, STAT3 is overexpressed leading to cell proliferation and inhibition of apoptosis. In this way, STAT3 activation is a viable target for treating cancer. XZH-5, a small molecule inhibitor of STAT3, works on the principle of interrupting dimerization by disrupting the interactions between the pTyr705 peptide and its associated pocket on the SH2 domain. In an attempt to optimize the binding of the inhibitor to the pTyr705 pocket, several derivatives of XZH-5 have been developed. This computational study seeks to investigate the structural aspects of the binding of these XZH-5 analogues to the pTyr705 pocket of the STAT3 SH2 domain using the RosettaLigand docking application. Docking results are compared to in vitro activity assays against multiple human cancer cell lines with the goal of identifying optimal XZH-5 analogues.

Computational modeling of STAT3 SH2 domain inhibition

249th National Meeting (2015)

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