The fatty acid binding proteins (FABPs) have been recognized as excellent new targets for the drug discovery of non-addictive antinociceptive and anti-inflammatory agents. FABPs have also been found to be overexpressed in certain cancers including breast and prostate cancers, playing key role in tumor growth. Thus, the inhibition of FABPs will provide a new approach to cancer chemotherapy. Recently, our research team solved the structures of the co-crystals of FABP5 and FABP7 with SB-FI-26, which is one of the lead compounds. These structures provided a structural basis for computationally designing new druggable FABP inhibitors with improved potency and selectivity. In the present work, the structures of two hit compounds, SB-FI-19 and SB-FI-31, arising from high-throughput in silico screening and actual FABP-binding assay in our previously reported study, was computationally analyzed (AutoDock 4.2) to design their analogs with improved binding affinity toward FABP5 and FABP7. Then, several most promising analogs were selected for chemical synthesis and binding affinity determination using a fluorescence displacement assay against FABPs 3, 5 and 7. The design, synthesis and biological evaluation of these novel FABP inhibitors, as well as their SAR will be presented.

SAR study of novel FABP inhibitors as antinociceptive, anti-inflammatory, and anticancer agents

255th National Meeting (2018)

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