7AUZ

LTA4 hydrolase in complex with compound LYS006

Summary for 7AUZ

• Entry DOI: 10.2210/pdb7auz/pdb
• Descriptor: Leukotriene A-4 hydrolase, ZINC ION, ACETATE ION, ... (7 entities in total)
• Functional Keywords: inhibitor, complex, hydrolase
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 1
• Total formula weight: 70618.51

Authors

Srinivas, H. (deposition date: 2020-11-03, release date: 2021-02-17, Last modification date: 2024-01-31)

Primary citation

Markert, C.,Thoma, G.,Srinivas, H.,Bollbuck, B.,Luond, R.M.,Miltz, W.,Walchli, R.,Wolf, R.,Hinrichs, J.,Bergsdorf, C.,Azzaoui, K.,Penno, C.A.,Klein, K.,Wack, N.,Jager, P.,Hasler, F.,Beerli, C.,Loetscher, P.,Dawson, J.,Wieczorek, G.,Numao, S.,Littlewood-Evans, A.,Rohn, T.A.
Discovery of LYS006, a Potent and Highly Selective Inhibitor of Leukotriene A 4 Hydrolase.
J.Med.Chem., 64:1889-1903, 2021

PubMed Abstract: The cytosolic metalloenzyme leukotriene A hydrolase (LTA4H) is the final and rate-limiting enzyme in the biosynthesis of pro-inflammatory leukotriene B (LTB). 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 LTB generation at low exposures , 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.

PubMed: 33592148
DOI: 10.1021/acs.jmedchem.0c01955

Experimental method

X-RAY DIFFRACTION (1.9 Å)