Abstract 1636: NMR discovery and molecular-basis of small molecule inhibitors of STAT3

Abstract

Abstract Hyperactivation of the signal transducer and activator of transcription 3 (STAT3) transcription factor is a critical molecular anomaly that promotes the constitutive transcription of pro-oncogenic genes in many tumor cells. Therefore, the direct inhibition of STAT3 signaling is a promising strategy to treat cancer. However, targeting transcription factors with small molecule drugs has proved to be challenging. To facilitate the generation of inhibitor leads with good ADME (absorption, distribution, metabolism, and excretion) attributes, we employed fragment-based screening by nuclear magnetic resonance spectroscopy (NMR) in conjunction with electrophoretic mobility shift assay (EMSA) to identify small molecule inhibitors of STAT3. The inhibitors confer specificity for STAT3; inhibit the activation and nuclear accumulation of STAT3; inhibit STAT3 transcription of cell cycle regulatory genes and the proliferation of STAT3-dependent cancer cell lines. We have used two-dimensional methyl NMR of STAT3 to reveal atomic resolution insights on the basis for inhibition. Our results establish an innovative approach to targeting STAT3 that may also be applied to other transcription factors associated with cancer and other diseases. Citation Format: Andrew T. Namanja, Ralf Buettner, Richard Jove, Yuan Chen. NMR discovery and molecular-basis of small molecule inhibitors of STAT3. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1636. doi:10.1158/1538-7445.AM2014-1636