9G0U

Human LTC4 synthase in complex with AZD9898

This is a non-PDB format compatible entry.

Summary for 9G0U

• Entry DOI: 10.2210/pdb9g0u/pdb
• Descriptor: Leukotriene C4 synthase, SULFATE ION, PALMITIC ACID, ... (7 entities in total)
• Functional Keywords: ltc4s, inhibitor, lyase
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 1
• Total formula weight: 23132.61

Authors

Srinivas, H. (deposition date: 2024-07-08, release date: 2025-02-26, Last modification date: 2025-03-05)

Primary citation

Thoma, G.,Miltz, W.,Waelchli, R.,Orain, D.,Spanka, C.,Decoret, O.,Wolf, R.M.,Hurley, B.,Cheung, A.K.,Sandham, D.A.,Honda, A.,Tichkule, R.,Chen, X.,Patel, T.,Labbe-Giguere, N.,Tan, K.L.,Springer, C.,Manchester, J.,Culshaw, A.J.,Hunt, P.,Srinivas, H.,Penno, C.A.,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, E.J.,Rohn, T.A.
Discovery of GJG057, a Potent and Highly Selective Inhibitor of Leukotriene C4 Synthase.
J.Med.Chem., 68:4721-4742, 2025

PubMed Abstract: Leukotriene C4 synthase (LTC4S) is a glutathione -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 ), which exhibits 20-fold improved potency (IC = 44 nM) versus clinical candidate AZD9898 (IC = 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.

PubMed: 39960261
DOI: 10.1021/acs.jmedchem.4c02897

Experimental method

X-RAY DIFFRACTION (2.5 Å)