Genentech, Inc. , 1 DNA Way , South San Francisco , California 94080 , United States.
J Med Chem. 2018 Mar 22;61(6):2227-2245. doi: 10.1021/acs.jmedchem.7b01712. Epub 2018 Feb 23.
Bruton's tyrosine kinase (Btk) is a nonreceptor cytoplasmic tyrosine kinase involved in B-cell and myeloid cell activation, downstream of B-cell and Fcγ receptors, respectively. Preclinical studies have indicated that inhibition of Btk activity might offer a potential therapy in autoimmune diseases such as rheumatoid arthritis and systemic lupus erythematosus. Here we disclose the discovery and preclinical characterization of a potent, selective, and noncovalent Btk inhibitor currently in clinical development. GDC-0853 (29) suppresses B cell- and myeloid cell-mediated components of disease and demonstrates dose-dependent activity in an in vivo rat model of inflammatory arthritis. It demonstrates highly favorable safety, pharmacokinetic (PK), and pharmacodynamic (PD) profiles in preclinical and Phase 2 studies ongoing in patients with rheumatoid arthritis, lupus, and chronic spontaneous urticaria. On the basis of its potency, selectivity, long target residence time, and noncovalent mode of inhibition, 29 has the potential to be a best-in-class Btk inhibitor for a wide range of immunological indications.
布鲁顿酪氨酸激酶（Btk）是一种非受体细胞质酪氨酸激酶，分别参与 B 细胞和髓样细胞的激活，是 B 细胞和 Fcγ 受体的下游分子。临床前研究表明，抑制 Btk 活性可能为类风湿关节炎和系统性红斑狼疮等自身免疫性疾病提供一种潜在的治疗方法。在此，我们披露了一种正在临床开发中的强效、选择性和非共价 Btk 抑制剂的发现和临床前特征。GDC-0853（化合物 29）抑制 B 细胞和髓样细胞介导的疾病成分，并在体内大鼠炎症性关节炎模型中表现出剂量依赖性活性。在正在进行的类风湿关节炎、狼疮和慢性自发性荨麻疹患者的临床前和 2 期研究中，29 表现出极好的安全性、药代动力学（PK）和药效动力学（PD）特征。基于其效力、选择性、长的靶标停留时间和非共价抑制模式，29 有可能成为广泛免疫适应症的同类最佳 Btk 抑制剂。
