Nathalie Wack

Novartis (Switzerland)

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Till A. Röhn

Novartis (Switzerland)

Franziska Hasler

Novartis (Switzerland)

Shin Numao

Novartis (Switzerland)

Carlos A. Penno

Novartis (Switzerland)

Srinivas Honnappa

Novartis (Switzerland)

Romain M. Wolf

Novartis (Switzerland)

Petra Jäger

Novartis (Switzerland)

Wolfgang Miltz

Novartis (Switzerland)

Beatrice Urban

Novartis (Switzerland)

Christian Bergsdorf

Novartis Institutes for BioMedical Research

Cooperative Institutions

Novartis (Switzerland)

Novartis Institutes for BioMedical Research

Novartis (United States)

Novartis (France)

University of Basel

Novartis (United Kingdom)

Centre National de la Recherche Scientifique

Inserm

Scripps Research Institute

Institut thématique Immunologie, inflammation, infectiologie et microbiologie

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Adriforant is a functional antagonist of histamine receptor 4 and attenuates itch and skin inflammation in mice

European Journal of Pharmacology (2023)

Özge Uluçkan Sandro Bruno Yichen Wang Nathalie Wack Jenny Wilzopolski

Histamine H4 receptor

Thioperamide

10.1016/j.ejphar.2023.175533

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Citations (5)

Comment on “An extracellular matrix fragment drives epithelial remodeling and airway hyperresponsiveness”

Science Translational Medicine (2019)

Carlos A. Penno Nathalie Wack Claire Laguerre Franziska Hasler Shin Numao

Increased airway hyperresponsiveness and epithelial remodeling in asthmatic LTA 4 H-KO mice may be mediated by CysLTs rather than elevated tripeptide PGP.

Airway hyperresponsiveness

Tripeptide

Tissue Remodeling

10.1126/scitranslmed.aav4538

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

Journal of Medicinal Chemistry (2025)

Gebhard Thoma Wolfgang Miltz Rudolf Waelchli David Orain Carsten Spanka

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.

Leukotriene C4

10.1021/acs.jmedchem.4c02897

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Feasibility and physiological relevance of designing highly potent aminopeptidase-sparing leukotriene A4 hydrolase inhibitors

Scientific Reports (2017)

Shin Numao Franziska Hasler Claire Laguerre Srinivas Honnappa Nathalie Wack

Leukotriene A4 Hydrolase (LTA4H) is a bifunctional zinc metalloenzyme that comprises both epoxide hydrolase and aminopeptidase activity, exerted by two overlapping catalytic sites. The epoxide hydrolase function of the enzyme catalyzes the biosynthesis of the pro-inflammatory lipid mediator leukotriene (LT) B4. Recent literature suggests that the aminopeptidase function of LTA4H is responsible for degradation of the tripeptide Pro-Gly-Pro (PGP) for which neutrophil chemotactic activity has been postulated. It has been speculated that the design of epoxide hydrolase selective LTA4H inhibitors that spare the aminopeptidase pocket may therefore lead to more efficacious anti-inflammatory drugs. In this study, we conducted a high throughput screen (HTS) for LTA4H inhibitors and attempted to rationally design compounds that would spare the PGP degrading function. While we were able to identify compounds with preference for the epoxide hydrolase function, absolute selectivity was not achievable for highly potent compounds. In order to assess the relevance of designing such aminopeptidase-sparing LTA4H inhibitors, we studied the role of PGP in inducing inflammation in different settings in wild type and LTA4H deficient (LTA4H KO) animals but could not confirm its chemotactic potential. Attempting to design highly potent epoxide hydrolase selective LTA4H inhibitors, therefore seems to be neither feasible nor relevant.

Epoxide hydrolase 2

Leukotriene B4

Hydrolase

10.1038/s41598-017-13490-1

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Citations (31)

Discovery of LYS006, a Potent and Highly Selective Inhibitor of Leukotriene A₄ Hydrolase

Journal of Medicinal Chemistry (2021)

Christian Märkert Gebhard Thoma Srinivas Honnappa Birgit Bollbuck Rainer M. Lüönd

The cytosolic metalloenzyme leukotriene A

Leukotriene B4

10.1021/acs.jmedchem.0c01955

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Citations (24)