Discovery of LOU064 (Remibrutinib), a Potent and Highly Selective Covalent Inhibitor of Bruton’s Tyrosine Kinase

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.

布鲁顿酪氨酸激酶（BTK），作为一种细胞质酪氨酸激酶，在免疫应答中扮演核心角色，并被视为治疗自身免疫性疾病的有力靶点。目前市场上销售的共价BTK抑制剂的应用局限于肿瘤学指征，这与其亚优的激酶选择性有关。本文详细阐述了LOU064（雷米布图林，25号化合物）的发现及其临床前特性，LOU064是一种高效、高度选择性的共价BTK抑制剂。由于能够与BTK的非活性构象结合，LOU064展现出卓越的激酶选择性，有望成为同类最佳共价BTK抑制剂，用于自身免疫性疾病的治疗。该化合物在体内实验中表现出强大的靶点占有率，EC90值为1.6 mg/kg，并在大鼠胶原诱导性关节炎模型中显示出剂量依赖性的疗效。目前，LOU064正在进行针对慢性自发性荨麻疹和舍格伦综合征的2期临床试验。