Markert, Christian, Thoma, Gebhard, Srinivas, Honnappa, Bollbuck, Birgit, Lueoend, Rainer Martin, Miltz, Wolfgang, Waelchli, Rudolf, Wolf, Romain, Hinrichs, Juergen, Bergsdorf, Christian, Azzaoui, Kamal, Penno, Carlos, Klein, Kai, Wack, Nathalie, Jaeger, Petra, Hasler, Franziska, Beerli, Christian, Loetscher, Pius, Dawson King, Janet, Wieczorek, Grazyna, Numao, Shin, Littlewood-Evans, Amanda and Roehn, Till (2021) Discovery of LYS006, a Potent and Highly Selective Inhibitor of Leukotriene A4 Hydrolase. Journal of medicinal chemistry.

Abstract

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.

Item Type:	Article
Keywords:	LTA4H, fragment screen, X-rays, inhibitors, solubility, rodent models, pharmacodynamics, clinical candidate.
Date Deposited:	05 Mar 2021 00:45
Last Modified:	05 Mar 2021 00:45
URI:	https://oak.novartis.com/id/eprint/43803