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


Journal of Medicinal Chemistry


Christian Markert, Gebhard Thoma, Honnappa Srinivas, Birgit Bollbuck, Rainer M. Lüönd, Wolfgang Miltz, Rudolf Wälchli, Romain Wolf, Jürgen Hinrichs, Christian Bergsdorf, Kamal Azzaoui,b Carlos A. Penno, Kai Klein, Nathalie Wack, Petra Jäger, Franziska Hasler, Christian Beerli, Pius Loetscher, Janet Dawson, Grazyna Wieczorek, Shin Numao, Amanda Littlewood-Evans, and Till A. Röhn



The cytosolic metalloenzyme leukotriene A4 hydrolase (LTA4H) is the final and rate-limiting enzyme in the biosynthesis of pro-inflammatory leukotriene B4 (LTB4). Preclinical studies have validated this enzyme as an attractive drug target in chronic inflammatory diseases. Despite several attempts, no LTA4H inhibitor has reached the market, yet. Herein, we disclose the discovery and preclinical profile of LYS006, a highly potent and selective LTA4H inhibitor. A focused fragment screen identified hits that could be cocrystallized with LTA4H and inspired a fragment merging. Further optimization led to chiral amino acids and ultimately to LYS006, a picomolar LTA4H inhibitor with exquisite whole blood potency and long-lasting pharmacodynamic effects. Due to its high selectivity and its ability to fully suppress LTB4 generation at low exposures in vivo, LYS006 has the potential for a best-in-class LTA4H inhibitor and is currently investigated in phase II clinical trials in inflammatory acne, hidradenitis suppurativa, ulcerative colitis, and NASH.

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