Abstract 1346: Discovery of novel MSK1 inhibitors with hybrid virtual screening and structure-based drug design

Abstract

Abstract Mitogen- and stress-activated protein kinase 1 (MSK1) is a serine/threonine kinase that is involved in gene transcription regulation and pro-inflammatory cytokine stimulation. MSK1 is an attractive target for the treatment of chronic inflammatory diseases. Currently, no small molecule inhibitor has been identified that specifically targets MSK1 and only H-89 is a known inhibitor. In this study, we performed hybrid virtual screening (HVS) to identify novel small molecule inhibitors that target MSK1. For the screening, we used the active conformation of the C-terminal kinase domain of the dual kinase as the protein template. Computational screening of several well-known compound databases, including the FDA, Natural Product, ZINC all purchasable and PDB ligands databases, revealed 40 potential leads. We tested 11 lead compounds and found 5 that showed substantial in vitro inhibitory activity against MSK1. These results illustrated that our computational screening processes greatly enhanced the success rate of virtual screening. The high-performing HVS protocols were especially successful to retrieve thousands of promising new leads from millions of compounds in conjunction with structure-based drug design and then to further select true hits from the majority of high-scoring decoys. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1346. doi:10.1158/1538-7445.AM2011-1346