Discovery of LYS006, a Potent and Highly Selective Inhibitor of Leukotriene A₄ Hydrolase

Abstract

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.

Current Status of the Use of Multifunctional Enzymes as Anti-Cancer Drug Targets

“…During this time, several inhibitors of LTA4H have been proposed, and five of those molecules have reached the early clinical development stage, although none of the clinical trials has targeted cancer patients [102]. Of these, only two, Acebilustat from Celtaxsys [104] and LYS006 from Novartis [105] (Figure 12), remain in active clinical development. Acebilustat completed Phase 2 clinical trials for cystic fibrosis (NCT02443688 [106]) and for Acne Vulgaris (NCT02385760 [107]).…”

“…The current status of the development of inhibitors targeting the four enzymes described in this review is summarized in Table 1. 3PO [46] yes [46] yes [46] no PFK15 [48] yes [48] yes [48] no PFK158 [48] yes [49] yes [49] NCT02044861 [50] PFK-2 activity of PFKFB4 5MPN [51] yes [51] yes [51] no ATIC AICAR TFase BW1540 [57] no no no AICAR TFase BW2315 [57] no no no AICAR TFase LSN3213128 [66] yes [66,67] yes [66,67] no LTA 4 H epoxide hydrolase and aminopeptidase activities Acebilustat no available data no available data no (1) epoxide hydrolase and aminopeptidase LYS006 [105] yes [105] yes [105] no (1) epoxide hydrolase RH00633 [112] yes [112] no no…”

Present and future trends of biologic therapies and small molecules in hidradenitis suppurativa

“…LYS006 is a highly potent and selective LTA4H inhibitor with high whole blood potency and long-lasting pharmacodynamic effects 50 .…”

“…Leukotriene A4 hydrolase is a cytosolic metalloenzyme involved in the biosynthesis of pro-inflammatory leukotriene B4 (LTB4). Furthermore, LTB4 is a strong inflammatory mediator engaged in innate and adaptative immune responses that has an important role in the recruitment and activation of neutrophils 50 .…”

Clinical Implementation of Biologics and Small Molecules in the Treatment of Hidradenitis Suppurativa

“…LYS006 is small molecule-selective leukotriene A4 hydrolase inhibitor [ 90 ]. A Phase II clinical study to assess the efficacy and safety in patients with moderate-to-severe HS is currently being conducted (NCT03827798).…”