Monocarbonyl Curcumin Analogues: Heterocyclic Pleiotropic Kinase Inhibitors That Mediate Anticancer Properties

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• 作者：Andrew Brown ; Qi Shi ; Terry W. Moore ; Younghyoun Yoon ; Andrew Prussia ; Clinton Maddox ; Dennis C. Liotta ; Hyunsuk Shim ; James P. Snyder
• 刊名：Journal of Medicinal Chemistry
• 出版年：2013
• 出版时间：May 9, 2013
• 年：2013
• 卷：56
• 期：9
• 页码：3456-3466
• 全文大小：640K
• 年卷期：v.56,no.9(May 9, 2013)
• ISSN：1520-4804

文摘

Curcumin is a biologically active component of curry powder. A structurally related class of mimetics possesses similar anti-inflammatory and anticancer properties. Mechanism has been examined by exploring kinase inhibition trends. In a screen of 50 kinases relevant to many forms of cancer, one member of the series (4, EF31) showed 鈮?5% inhibition for 10 of the enzymes at 5 渭M, while 22 of the proteins were blocked at 鈮?0%. IC₅₀ values for an expanded set of curcumin analogues established a rank order of potencies, and analyses of IKK尾 and AKT2 enzyme kinetics for 4 revealed a mixed inhibition model, ATP competition dominating. Our curcumin mimetics are generally selective for Ser/Thr kinases. Both selectivity and potency trends are compatible with protein sequence comparisons, while modeled kinase binding site geometries deliver a reasonable correlation with mixed inhibition. Overall, these analogues are shown to be pleiotropic inhibitors that operate at multiple points along cell signaling pathways.