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Last update 08 May 2025

LTC4S

Last update 08 May 2025

Basic Info

Synonyms

Glutathione S-transferase LTC4, Leukotriene C4 synthase, Leukotriene-C(4) synthase

+ [4]

Introduction

Catalyzes the conjugation of leukotriene A4 with reduced glutathione (GSH) to form leukotriene C4 with high specificity (PubMed:23409838, PubMed:27365393, PubMed:27791009, PubMed:7937884, PubMed:9153254). Can also catalyze the transfer of a glutathionyl group from glutathione (GSH) to 13(S),14(S)-epoxy-docosahexaenoic acid to form maresin conjugate in tissue regeneration 1 (MCTR1), a bioactive lipid mediator that possess potent anti-inflammatory and proresolving actions (PubMed:27791009).

Drugs associated with LTC4S

GJG-057

Target

LTC4S

Mechanism

LTC4S inhibitors

Active Org.

Novartis Pharma AG

Originator Org.

Novartis Pharma AG

Active Indication

Asthma

Inactive Indication-

Drug Highest PhasePreclinical

First Approval Ctry. / Loc.-

First Approval Date20 Jan 1800

AZD-9898

Target

LTC4S

Mechanism

LTC4S inhibitors

Active Org.-

Originator Org.

Orexo AB

Active Indication-

Inactive Indication

Asthma [+1]

Drug Highest PhaseDiscontinued

First Approval Ctry. / Loc.-

First Approval Date20 Jan 1800

Clinical Trials associated with LTC4S

NCT03140072

/ TerminatedPhase 1

A Phase I, Randomized, Placebo-Controlled Study to Assess the Safety, Tolerability, Pharmacokinetics, Pharmacodynamics and Food Effect of Single and Multiple Ascending Oral Doses of AZD9898 in Healthy Volunteers and Asthma Patients.

In this integrated, multi-part, Phase I study, the safety, tolerability, food effect, pharmacokinetic (PK) and pharmacodynamic (PD) properties of single and repeated doses of AZD9898 will be investigated.

Start Date10 May 2017

Sponsor / Collaborator

AstraZeneca PLC

[+1]

100 Clinical Results associated with LTC4S

100 Translational Medicine associated with LTC4S

0 Patents (Medical) associated with LTC4S

449

Literatures (Medical) associated with LTC4S

01 May 2025·Journal of Allergy and Clinical Immunology: Global

Acute/baseline ratios of all 3 MC mediator metabolites can enhance diagnosis and management of mast cell activation syndrome

Article

Author: Taylor, Adela ; Butterfield, Joseph H

BackgroundMast cell (MC) activation syndrome (MCAS) can be a challenge to diagnose and treat despite the near continuous appearance of publications outlining specific criteria. Follow-up of the clinical responses to treatment is often lacking, and confirmation that leukotriene C₄ (LTC₄) is an active participant in MCAS has been overlooked.ObjectiveThree patients with MCAS characterized by anaphylaxis are presented to illustrate (1) the value of contemporaneous urinary mediator sampling during MCAS in addition to serum tryptase measurements and (2) substantiation of the fact that not only can LTC₄ (measured metabolite LTE₄) be the highest metabolite measured, but (3) blockade of the LTE₄ receptor can contribute to symptom prevention.MethodThe study methods comprised clinical review and quantitation of acute and baseline levels of tryptase and urinary MC mediators.ResultsThe cases of 3 patients with MCAS are reviewed. In the first case, vespid sting-induced anaphylaxis was associated with a marked increase in the LTE₄ excretion. The addition of montelukast was instituted, and subsequent stings did not evoke symptoms. In the second case, acute measurements showed substantial increased levels of (2,3-dinor)-11β-prostaglandin F_2α, and LTE₄. The addition of aspirin plus montelukast prevented subsequent attacks. The third case documents a perioperative anaphylactic event with an acute/baseline LTE₄ ratio far higher than those of tryptase or other metabolites.ConclusionsThe value of measuring all 3 MC mediator metabolites during MCAS should not be overlooked. These measurements can facilitate the successful prevention of attacks. Furthermore, results from these tests show that histamine is often a minor player, whereas acute/baseline levels of the metabolites of LTC₄ and prostaglandin D₂ are frequently much higher, warranting nonantihistamine treatment.

27 Feb 2025·Journal of Medicinal Chemistry

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

Article

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

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.

01 Feb 2025·Pharmaceutical Research

Structure Bioinformatics of Six Human Integral Transmembrane Enzymes and their AlphaFold3 Predicted Water-Soluble QTY Analogs: Insights into FACE1 and STEA4 Binding Mechanisms

Article

Author: Pan, Emily ; Zhang, Shuguang ; Chen, Edward

AbstractObjectiveHuman integral membrane enzymes are essential for catalyzing a wide range of biochemical reactions and regulating key cellular processes. However, studying these enzymes remains challenging due to their hydrophobic nature, which necessitates the use of detergents. This study explores whether applying the QTY code can reduce the hydrophobicity of these enzymes while preserving their structures and functions, thus facilitating bioinformatics analysis of six key integral membrane enzymes: MGST2, LTC4S, PTGES, FACE1, STEA4, and SCD.MethodsThe water-soluble QTY analogs of the six membrane enzymes were predicted using AlphaFold3. The predicted structures were superposed with CyroEM determined native structures in PyMOL to observe changes in structure and protein-ligand binding ability.ResultsThe native membrane enzymes superposed well with their respective QTY analogs, with the root mean square deviation (RMSD) ranging from 0.273 Å to 0.875 Å. Surface hydrophobic patches on the QTY analogs were significantly reduced. Importantly, the protein-ligand interactions in FACE1 and STEA4 were largely preserved, indicating maintained functionality.ConclusionOur structural bioinformatics studies using the QTY code and AlphaFold3 not only provide the opportunities of designing more water-soluble integral membrane enzymes, but also use these water-soluble QTY analogs as antigens for therapeutic monoclonal antibody discovery to specifically target the key integral membrane enzymes.

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