Discovery of LYS006, a Potent and Highly Selective Inhibitor of Leukotriene A4 Hydrolase

ABSTRACT: The cytosolic metalloenzyme Leukotriene A4 Hydrolase (LTA4H) is the final and rate-limiting enzyme in the biosynthesis of pro-inflammatory lipid mediator Leukotriene B4 (LTB4). Genetic deletion as well as pharmacological inhibi-tion of LTA4H in preclinical models have validated this enzyme as an attractive drug target in chronic inflammatory dis-eases. Despite several attempts by different pharmaceutical companies, no LTA4H inhibitor has yet reached the market. Herein, we disclose the discovery and preclinical profile of LYS006, a highly potent and selective LTA4H inhibitor. A fo-cused DSF screen for binders of LTA4H afforded fragments 1 and 2 that could be co-crystallized with LTA4H and inspired a fragment merging. Further optimization led to chiral amino acids and ultimately to LYS006/(S)-22, a picomolar LTA4H inhibitor with exquisite whole blood potency (IC90 = 143 nM) and long-lasting in vivo pharmacodynamic effects. Due to its high selectivity and its ability to suppress LTB4 generation entirely in vivo at low exposures, LYS006 has the potential for a best-in-class LTA4H inhibitor and is currently being studied in phase II clinical trials in inflammatory acne, hidradenitis sup-purativa, ulcerative colitis and NASH