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Indirubin Core Structure Of Glycogen Synthase Kinase-3 Inhibitors As Novel Chemotype For Intervention With 5-lipoxygenase.

C. Pergola, N. Gaboriaud-Kolar, Nadine Jestädt, Stefanie König, M. Kritsanida, A. M. Schaible, Haokun Li, Ulrike Garscha, C. Weinigel, D. Barz, K. Albring, O. Huber, A. L. Skaltsounis, O. Werz
Published 2014 · Chemistry, Medicine

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The enzymes 5-lipoxygenase (5-LO) and glycogen synthase kinase (GSK)-3 represent promising drug targets in inflammation. We made use of the bisindole core of indirubin, present in GSK-3 inhibitors, to innovatively target 5-LO at the ATP-binding site for the design of dual 5-LO/GSK-3 inhibitors. Evaluation of substituted indirubin derivatives led to the identification of (3Z)-6-bromo-3-[(3E)-3-hydroxyiminoindolin-2-ylidene]indolin-2-one (15) as a potent, direct, and reversible 5-LO inhibitor (IC50 = 1.5 μM), with comparable cellular effectiveness on 5-LO and GSK-3. Together, we present indirubins as novel chemotypes for the development of 5-LO inhibitors, the interference with the ATP-binding site as a novel strategy for 5-LO targeting, and dual 5-LO/GSK-3 inhibition as an unconventional and promising concept for anti-inflammatory intervention.
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