Thoma, Gebhard, Orain, David, Spanka, Carsten, Decoret, Odile, Hurley, Brian, Cheung, Atwood, Sandham, David, Honda, Ayako, Tichkule, Ritesh, Chen, Xin2, Patel, Tajesh, Labbe-Giguere, Nancy, Tan, Kian, Manchester, John, Srinivas, Honnappa, Penno, Carlos, Numao, Shin, Schopfer, Ulrich, Jaeger, Petra-1, Wack, Nathalie, Hasler, Franziska, Sindelar, Miriam, Loetscher, Pius, Kiffe, Michael, Ren, Xiaojun, Subramanian, Khaushik, Growcott, Ellie and Roehn, Till (2025) Discovery of GJG057, a Potent and Highly Selective Inhibitor of Leukotriene C4 Synthase. Journal of medicinal chemistry, 68. pp. 4721-4742.

Abstract

Leukotriene C4 synthase (LTC4S) is a glutathione S-transferase that mediates the biosynthesis of cysteinyl leukotriene C4 (LTC4). Cysteinyl leukotrienes (CysLTs) are lipid mediators that drive type 2 inflammation, bronchoconstriction, and itch. LTC4S represents an attractive drug target for the treatment of allergic inflammatory diseases, but to date, no LTC4S inhibitor has been tested in patients. Herein, we disclose the discovery and preclinical profiling of the highly selective, oral LTC4S inhibitor GJG057 (compound 1), which exhibits 20-fold improved potency (IC50 = 44 nM) versus clinical candidate AZD9898 (IC50 = 900 nM) in a human whole blood LTC4 release assay. GJG057 showed efficacy in a murine asthma exacerbation model as well as in a murine mastoparan-induced skin challenge PK/PD model and was profiled in GLP toxicology studies with up to 16 weeks duration. Despite its promising properties, GJG057 was not progressed into clinical trials as an oral drug.

Item Type:	Article
Date Deposited:	08 Apr 2025 00:45
Last Modified:	08 Apr 2025 00:45
URI:	https://oak.novartis.com/id/eprint/54572