9G0V の概要
| エントリーDOI | 10.2210/pdb9g0v/pdb |
| 関連するPDBエントリー | 9GOU |
| 分子名称 | Leukotriene C4 synthase, PALMITIC ACID, DODECYL-BETA-D-MALTOSIDE, ... (5 entities in total) |
| 機能のキーワード | ltc4s, inhibitor, lyase |
| 由来する生物種 | Homo sapiens (human) |
| タンパク質・核酸の鎖数 | 1 |
| 化学式量合計 | 19256.80 |
| 構造登録者 | |
| 主引用文献 | 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 Cited by 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: 39960261DOI: 10.1021/acs.jmedchem.4c02897 主引用文献が同じPDBエントリー |
| 実験手法 | X-RAY DIFFRACTION (2.784 Å) |
構造検証レポート
検証レポート(詳細版)
をダウンロード
をダウンロード
