9g0u
Human LTC4 synthase in complex with AZD9898
Structural highlights
DiseaseLTC4S_HUMAN Defects in LTC4S are the cause of leukotriene C4 synthase deficiency (LTC4 synthase deficiency) [MIM:246530. LTC4 synthase deficiency is a fatal neurometabolic developmental disorder. It is associated with muscular hypotonia, psychomotor retardation, failure to thrive, and microcephaly. FunctionLTC4S_HUMAN Catalyzes the conjugation of leukotriene A4 with reduced glutathione to form leukotriene C4. Publication Abstract from PubMedLeukotriene 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 (IC(50) = 44 nM) versus clinical candidate AZD9898 (IC(50) = 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. Discovery of GJG057, a Potent and Highly Selective Inhibitor of Leukotriene C4 Synthase.,Thoma G, Miltz W, Waelchli R, Orain D, Spanka C, Decoret O, Wolf RM, Hurley B, Cheung AK, Sandham DA, Honda A, Tichkule R, Chen X, Patel T, Labbe-Giguere N, Tan KL, Springer C, Manchester J, Culshaw AJ, Hunt P, Srinivas H, Penno CA, Ferrand S, Numao S, Schopfer U, Jager P, Wack N, Hasler F, Urban B, Sindelar M, Loetscher P, Kiffe M, Ren X, Nicklin P, White K, Subramanian K, Liu H, Growcott EJ, Rohn TA J Med Chem. 2025 Feb 17. doi: 10.1021/acs.jmedchem.4c02897. PMID:39960261[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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