Design, synthesis, and biological evaluation of novel EF24 and EF31 analogs as potential IκB kinase β inhibitors for the treatment of pancreatic cancer

Given the important role that inhibitory kappa B (I kappa B) kinase beta (IKK beta) plays in pancreatic cancer (PC) development and progression, inhibitors targeting IKK beta are believed to be increasingly popular as novel anti-PC therapies. Two synthetic molecules, named EF24 and EF31, exhibited favorable potential in terms of inhibition of both IKK beta activity and PC cell proliferation. Aiming to enhance their cellular efficacy and to analyze their structure-activity relationship, four series of EF24 and EF31 analogs were designed and synthesized. Through kinase activity and vitality screening of cancer cells, D6 displayed excellent inhibition of both IKK beta activity and PC cell proliferation. Additionally, multiple biological evaluations showed that D6 was directly bound to IKK beta and significantly suppressed the activation of the IKK beta/nuclear factor kappa B pathway induced by tumor necrosis factor-alpha, as well as effectively inducing cancer cell apoptosis. Moreover, molecular docking and molecular dynamics simulation analysis indicated that the dominant force between D6 and IKK beta comprised hydrophobic interactions. In conclusion, D6 may be a promising therapeutic agent for PC treatment and it also provides a structural lead for the design of novel IKK beta inhibitors.