Structure-based development of novel small-molecule kinase inhibitors and efficient synthesis of frutinone a derivatives

Abstract

To effectively overcome various problems of drug development process, it is very important to obtain struc-turally diverse & novel scaffolds at the discovery stage. Although the high-throughput screening technology has been widely used for this purpose, it consumes a lot of cost and time with the increased size of a screening library. Therefore, some rational approaches such as structure-based drug design have attracted considerable attention from research groups. Herein, we focused on the development of small molecule inhibitors against 4 biological targets directly or indirectly connected to cancer. First of all, in order to find potent CYP1A2 inhibitor based on natural products, we have developed an efficient method through a palladium-catalyzed C-H activation/carbonylation and consequently identified a frutinone A derivative having a 2-fold higher potency. Moreover, a variety of structure-based drug design techniques which contain de nove design, fragment linking and structure-based virtual screening, efficiently provided both novel $IKK \beta$ inhibitors with an anti-inflammatory effect in cellular levels and potent $GSK3 \beta$ inhibitors with high selectivity for broad kinases. Finally, structure-based virtual screening and docking studies have shown that coumarin scaffold can serve as a new template for the development of fluorescent ALK inhibitors. Taken together, we expect that structure-based drug design could offer us a promising opportunity for discover structurally diverse and novel compounds as a starting point for drug development.