Discovery of ML351, a Potent and Selective Inhibitor of Human 15-Lipoxygenase-1

Excerpt

Lipoxygenases (e.g. 5, 12 and 15-LOX-1) are implicated in a number of human diseases, with reticulocyte 15-Lipoxygenase-1 (15-LOX-1 or 12/15-LOX) being specifically involved in cancer, atherosclerosis, and neurodegenerative conditions, such as stroke [1-9]. Despite the potential therapeutic relevance of this target, few potent, selective and cell-active inhibitors have been reported. Toward this end, we employed a quantitative high-throughput (qHTS) screen against ∼74,000 small molecules which led to the discovery of ML351, a novel chemotype for 15-LOX-1 inhibition, that displays nanomolar potency (IC₅₀ = 200 nM) and excellent selectivity (>250-fold) versus the related isozymes, 5-LOX, platelet 12-LOX, 15-LOX-2, ovine COX-1, and human COX-2. In addition, kinetic experiments were performed which indicate that this class of inhibitor is a tight binding, mixed inhibitor, which does not reduce the active-site ferric ion. Finally, ML351 protected against oxidative glutamate toxicity in mouse neuronal cells (HT-22) and significantly reduced infarct size in an in vivo mouse model for ischemic stroke. As such, ML351 represents the first report of a selective inhibitor of 15-LOX-1 with demonstrated in vivo activity in proof-of-concept models of stroke.