title: Monocarbonyl curcumin analogues: heterocyclic pleiotropic kinase inhibitors that mediate anticancer properties.
abstract: 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 ≥85% inhibition for 10 of the enzymes at 5 μM, while 22 of the proteins were blocked at ≥40%. IC50 values for an expanded set of curcumin analogues established a rank order of potencies, and analyses of IKKβ 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.
authors.affiliation: Winship Cancer Institute, Emory University, Atlanta, Georgia 30322, United States.
authors.forename: Andrew
authors.initials: A
authors.lastname: Brown
authors.forename: Qi
authors.initials: Q
authors.lastname: Shi
authors.forename: Terry W
authors.initials: TW
authors.lastname: Moore
authors.forename: Younghyoun
authors.initials: Y
authors.lastname: Yoon
authors.forename: Andrew
authors.initials: A
authors.lastname: Prussia
authors.forename: Clinton
authors.initials: C
authors.lastname: Maddox
authors.forename: Dennis C
authors.initials: DC
authors.lastname: Liotta
authors.forename: Hyunsuk
authors.initials: H
authors.lastname: Shim
authors.forename: James P
authors.initials: JP
authors.lastname: Snyder
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry* / Q000494:pharmacology*; D001665:Binding Sites; D045744:Cell Line, Tumor; D003474:Curcumin / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D020128:Inhibitory Concentration 50; D007700:Kinetics; D051379:Mice; D008958:Models, Molecular; D010766:Phosphorylation / Q000187:drug effects; D011487:Protein Conformation; D047428:Protein Kinase Inhibitors / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology*; D011494:Protein Kinases / Q000737:chemistry / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D013329:Structure-Activity Relationship
chemical_list: D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; D011494:Protein Kinases; D003474:Curcumin
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