Indirubin Core Structure of Glycogen Synthase Kinase‑3 Inhibitors as Novel Chemotype for Intervention with 5‑Lipoxygenase

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 (3<i>Z</i>)-6-bromo-3-[(3<i>E</i>)-3-hydroxyiminoindolin-2-ylidene]­indolin-2-one (<b>15</b>) 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