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. 2025 Feb 27;68(4):4721-4742.
doi: 10.1021/acs.jmedchem.4c02897. Epub 2025 Feb 17.

Discovery of GJG057, a Potent and Highly Selective Inhibitor of Leukotriene C4 Synthase

Gebhard Thoma  1 , Wolfgang Miltz  1 , Rudolf Waelchli  1 , David Orain  1 , Carsten Spanka  1 , Odile Decoret  1 , Romain M Wolf  1 , Brian Hurley  2 , Atwood K Cheung  2 , David A Sandham  2 , Ayako Honda  2 , Ritesh Tichkule  2 , Xin Chen  2 , Tajesh Patel  2 , Nancy Labbe-Giguere  2 , Kian L Tan  2 , Clayton Springer  2 , John Manchester  2 , Andrew J Culshaw  3 , Peter Hunt  3 , Honnappa Srinivas  4 , Carlos A Penno  4 , Sandrine Ferrand  4 , Shin Numao  4 , Ulrich Schopfer  4 , Petra Jäger  5 , Nathalie Wack  5 , Franziska Hasler  5 , Beatrice Urban  5 , Miriam Sindelar  5 , Pius Loetscher  5 , Michael Kiffe  6 , Xiaojun Ren  7 , Paul Nicklin  8 , Kevin White  9 , Khaushik Subramanian  9 , Haoyuan Liu  9 , Ellena J Growcott  9 , Till A Röhn  5
Affiliations

Discovery of GJG057, a Potent and Highly Selective Inhibitor of Leukotriene C4 Synthase

Gebhard Thoma et al. J Med Chem. .

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. Thus, 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 mastoparan-induced skin challenge PK/PD model and was profiled in GLP toxicology studies. Despite its promising properties, GJG057 was not progressed into clinical trials as an oral drug. Its potential as a topical drug is currently being evaluated.

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