2. Academic Validation
  3. Discovery of GJG057, a Potent and Highly Selective Inhibitor of Leukotriene C4 Synthase

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

  • J Med Chem. 2025 Feb 27;68(4):4721-4742. doi: 10.1021/acs.jmedchem.4c02897.
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

Affiliations

  • 1 Global Discovery Chemistry, Biomedical Research, Novartis Pharma AG, Basel 4002, Switzerland.
  • 2 Global Discovery Chemistry, Biomedical Research, Novartis Pharmaceuticals, Cambridge, Massachusetts 02139, United States.
  • 3 Global Discovery Chemistry, Novartis Horsham Research Centre, Horsham, West Sussex RH12 5AB, U.K.
  • 4 Discovery Sciences, Biomedical Research, Novartis Pharma AG, Basel 4002, Switzerland.
  • 5 Immunology Disease Area, Biomedical Research, Novartis Pharma AG, Basel 4002, Switzerland.
  • 6 PK Sciences, Biomedical Research, Novartis Pharma AG, Basel 4002, Switzerland.
  • 7 PK Sciences, Biomedical Research, Novartis Pharmaceuticals, East Hanover, New Jersey 07936, United States.
  • 8 Respiratory Disease Area, Novartis Horsham Research Centre, Horsham, West Sussex RH12 5AB, U.K.
  • 9 Global Health Disease Area, Biomedical Research, Novartis Pharmaceuticals, Cambridge, Massachusetts 02139, United States.
PMID: 39960261 DOI: 10.1021/acs.jmedchem.4c02897
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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