The cytosolic metalloenzyme leukotriene A₄ hydrolase (LTA4H) is the final and rate-limiting enzyme in the biosynthesis of pro-inflammatory leukotriene B₄ (LTB₄). Preclinical studies have validated this enzyme as an attractive drug target in chronic inflammatory diseases. Despite several attempts, no LTA4H inhibitor has reached the market, yet. Herein, we disclose the discovery and preclinical profile of LYS006, a highly potent and selective LTA4H inhibitor. A focused fragment screen identified hits that could be cocrystallized with LTA4H and inspired a fragment merging. Further optimization led to chiral amino acids and ultimately to LYS006, a picomolar LTA4H inhibitor with exquisite whole blood potency and long-lasting pharmacodynamic effects. Due to its high selectivity and its ability to fully suppress LTB₄ generation at low exposures in vivo, LYS006 has the potential for a best-in-class LTA4H inhibitor and is currently investigated in phase II clinical trials in inflammatory acne, hidradenitis suppurativa, ulcerative colitis, and NASH.

中文翻译：

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LYS006 的发现，一种强效且高选择性的白三烯 A4 水解酶抑制剂


胞质金属酶白三烯 A ₄水解酶 (LTA4H) 是促炎白三烯 B ₄ (LTB ₄ ) 生物合成中的最终限速酶。临床前研究已证实这种酶是慢性炎症性疾病中有吸引力的药物靶点。尽管进行了多次尝试，但尚未有 LTA4H 抑制剂进入市场。在此，我们公开了 LYS006 的发现和临床前概况，LYS006 是一种高效、选择性的 LTA4H 抑制剂。聚焦片段筛选确定了可以与 LTA4H 共结晶的命中，并激发了片段合并。进一步优化产生了手性氨基酸，并最终产生了 LYS006，这是一种皮摩尔 LTA4H 抑制剂，具有出色的全血效力和持久的药效作用。由于其高选择性以及在体内低暴露量下完全抑制 LTB ₄生成的能力，LYS006 具有成为同类最佳 LTA4H 抑制剂的潜力，目前正在进行炎症性痤疮、化脓性汗腺炎、溃疡性痤疮的 II 期临床试验。结肠炎和 NASH。