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

Overview

Journal J Med Chem

Publisher American Chemical Society

Specialty Chemistry

Date 2013 Apr 5

PMID 23550937

Citations 11

Authors

Andrew Brown

Qi Shi

Terry W Moore

Younghyoun Yoon

Andrew Prussia

Clinton Maddox

Dennis C Liotta

Hyunsuk Shim

James P Snyder

Affiliations

Soon will be listed here.

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.

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