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

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