Nowadays, drug design and development efforts are greatly focused on protein kinases to provide a more in-depth knowledge about them as one of the most successful targets for the treatment of different diseases. TANK-binding kinase 1 (TBK1) and IκB kinase subunit epsilon (IKK-ε) are highly homologous serine/threonine kinases that are involved in diverse cellular functions like innate immune response, tumorigenesis and development. The biology of TBK1 and IKK-ε is complicated and is not well understood. Some studies have showed that these kinases phosphorylate numerous targets that have a role in immune responses, inflammation, and proliferation.<br/>Recently, a few scaffolds have been reported as TBK1/ IKK-ε inhibitors but there is a great need to improve the selectivity of the inhibitors for these two highly homologous kinases. As a result, design and synthesis of highly potent and selective TBK1/ IKK-ε inhibitors is an interesting topic in medicinal chemistry and chemical biology. We started this project by inspiration of previously reported scaffolds and eventually designed and synthesized a library of non-covalent small molecule inhibitors of TBK1/ IKK-ε. Selectivity of the optimized molecules over around 300 kinases has been evaluated. The liver enzyme stability and pharmacokinetic property of best inhibitors were investigated in order to administer the inhibitor in an <i>in vivo</i> study. To improve the selectivity of inhibitors, a series of covalent inhibitors of TBK1 were designed and synthesized by taking advantage of the optimized structure as well chemical biology approaches. Additionally, the DNA construct of TBK1 has been prepared to make co-crystal structures with the optimized compound. Finally, the antiproliferative efficacy of compounds on multiple cancer cell lines and luciferase reporter signaling pathway is currently under investigation.

Medicinal chemistry and chemical biology approach in order to design and synthesize of TBK1/ IKK-ε small molecules inhibitors

2019 Spring National Meeting

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