RESUMEN
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.
Asunto(s)
Aminobutiratos/uso terapéutico , Antiinflamatorios/farmacología , Inhibidores Enzimáticos/uso terapéutico , Epóxido Hidrolasas/antagonistas & inhibidores , Piridinas/uso terapéutico , Aminobutiratos/síntesis química , Aminobutiratos/farmacocinética , Animales , Antiinflamatorios/síntesis química , Antiinflamatorios/farmacocinética , Artritis Experimental/tratamiento farmacológico , Perros , Descubrimiento de Drogas , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/farmacocinética , Femenino , Humanos , Inflamación/tratamiento farmacológico , Masculino , Ratones Endogámicos C57BL , Estructura Molecular , Piridinas/síntesis química , Piridinas/farmacocinética , Ratas Wistar , Relación Estructura-ActividadRESUMEN
Bruton's tyrosine kinase (BTK), a cytoplasmic tyrosine kinase, plays a central role in immunity and is considered an attractive target for treating autoimmune diseases. The use of currently marketed covalent BTK inhibitors is limited to oncology indications based on their suboptimal kinase selectivity. We describe the discovery and preclinical profile of LOU064 (remibrutinib, 25), a potent, highly selective covalent BTK inhibitor. LOU064 exhibits an exquisite kinase selectivity due to binding to an inactive conformation of BTK and has the potential for a best-in-class covalent BTK inhibitor for the treatment of autoimmune diseases. It demonstrates potent in vivo target occupancy with an EC90 of 1.6 mg/kg and dose-dependent efficacy in rat collagen-induced arthritis. LOU064 is currently being tested in phase 2 clinical studies for chronic spontaneous urticaria and Sjoegren's syndrome.
Asunto(s)
Agammaglobulinemia Tirosina Quinasa/antagonistas & inhibidores , Agammaglobulinemia Tirosina Quinasa/metabolismo , Descubrimiento de Drogas/métodos , Inhibidores de Proteínas Quinasas/metabolismo , Inhibidores de Proteínas Quinasas/farmacología , Agammaglobulinemia Tirosina Quinasa/química , Animales , Benzamidas/química , Benzamidas/metabolismo , Benzamidas/farmacología , Compuestos Bicíclicos Heterocíclicos con Puentes/química , Compuestos Bicíclicos Heterocíclicos con Puentes/metabolismo , Compuestos Bicíclicos Heterocíclicos con Puentes/farmacología , Cristalografía por Rayos X/métodos , Perros , Relación Dosis-Respuesta a Droga , Femenino , Humanos , Ratones , Unión Proteica/fisiología , Inhibidores de Proteínas Quinasas/química , Estructura Secundaria de Proteína , Estructura Terciaria de Proteína , Ratas , Ratas Endogámicas Lew , OvinosRESUMEN
Computer-aided ligand design is an active, challenging, and multidisciplinary research field that blends knowledge of biochemistry, physics, and computer sciences. Whenever it is possible to experimentally determine or to model the three-dimensional structure of a pharmacologically relevant enzyme or receptor, computational approaches can be used to design specific high-affinity ligands. This article describes methods, applications, and perspectives of computer-assisted ligand design.