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

• Published in: Drug design, development and therapy development and therapy, 2017-01, Vol.11, p.1439-1451
• Main Authors: Xie, Xuemeng, Tu, Jinfu, You, Heyi, Hu, Bingren
• Format: Article
• Language: English
• Subjects: Analogs; Anti-pancreatic cancer activity; Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Apoptosis; Apoptosis - drug effects; Benzylidene Compounds - chemical synthesis; Benzylidene Compounds - chemistry; Benzylidene Compounds - pharmacology; Cancer; Cancer therapies; Cell Line, Tumor; Cell proliferation; Cell Proliferation - drug effects; Cellular structure; Chemical compounds; Chromatography; Curcumin - analogs & derivatives; Curcumin - chemical synthesis; Curcumin - chemistry; Curcumin - pharmacology; FDA approval; Humans; Hydrophobicity; I-kappa B Kinase - antagonists & inhibitors; I-kappa B Kinase - metabolism; Inhibition; Inhibitors; IκB kinaseβ; Kinases; Mass spectrometry; Metabolism; Molecular docking; Molecular Docking Simulation; Molecular dynamics; Molecular dynamics simulation; NF-kappa B - metabolism; NMR; Nuclear magnetic resonance; Original Research; Pancreatic cancer; Pancreatic Neoplasms - drug therapy; Pancreatic Neoplasms - enzymology; Pharmacology; Phosphorylation; Piperidones - chemical synthesis; Piperidones - chemistry; Piperidones - pharmacology; Protein Kinase Inhibitors - chemical synthesis; Protein Kinase Inhibitors - chemistry; Protein Kinase Inhibitors - pharmacology; Scientific imaging; Simulation analysis; Structure-Activity Relationship; Tumor Necrosis Factor-alpha - metabolism; Tumor necrosis factor-TNF; Tumor necrosis factor-α; Tumorigenesis
• ISSN: 1177-8881; 1177-8881
• DOI: 10.2147/DDDT.S133172

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.