J Med Chem. 2021 Feb 25;64(4):1889-1903. doi: 10.1021/acs.jmedchem.0c01955. Epub 2021 Feb 16.
The cytosolic metalloenzyme leukotriene A hydrolase (LTA4H) is the final and rate-limiting enzyme in the biosynthesis of pro-inflammatory leukotriene B (LTB). 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 LTB generation at low exposures , 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.
胞质金属酶白三烯 A 水解酶 (LTA4H) 是促炎白三烯 B (LTB) 生物合成中的最后一个限速酶。临床前研究已经证实，该酶是慢性炎症性疾病中一种有吸引力的药物靶点。尽管进行了多次尝试，但仍没有 LTA4H 抑制剂上市。本文披露了 LYS006 的发现和临床前特征，LYS006 是一种高活性和选择性的 LTA4H 抑制剂。我们通过聚焦片段筛选确定了可以与 LTA4H 共结晶的化合物，并启发了片段融合。进一步优化导致了手性氨基酸的出现，最终得到了 LYS006，这是一种对 LTA4H 具有皮摩尔级抑制活性的化合物，具有出色的全血效力和持久的药效作用。由于其高选择性和在低暴露时能够完全抑制 LTB 的生成，LYS006 有可能成为一流的 LTA4H 抑制剂，目前正在炎症性痤疮、化脓性汗腺炎、溃疡性结肠炎和 NASH 的 II 期临床试验中进行研究。
