Inhibition of Btk with CC-292 Provides Early Pharmacodynamic Assessment of Activity in Mice and Humans
Inhibition of Btk with CC-292 Provides Early Pharmacodynamic Assessment of Activity in Mice and Humans
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DOI：
10.1124/jpet.113.203489
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发表时间：
2013-08-01
影响因子：
3.5
通讯作者：
Westlin, William F.
中科院分区：
文献类型：
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作者：
Evans, Erica K.;Tester, Richland;Westlin, William F.
抑制B细胞受体(BCR)信号转导的靶向治疗已成为治疗自身免疫性疾病和B细胞恶性肿瘤的有效药物。Bruton‘s酪氨酸激酶(BTK)通过BCR信号通路在B细胞的发育和激活中起关键作用，是治疗B细胞活性异常疾病的新靶点。N-(3-(5-fluoro-2-(4-(2-methoxyethoxy)phenylamino)pyrimidin-4-ylamino)phenyl)丙烯酰胺(CC-292)是一种高度选择性的共价BTK抑制剂，已建立了一种灵敏的定量检测CC-292-BTK结合的方法。这种翻译药效学分析伴随着CC-292药物发现和开发的每一步。这些研究表明，CC-292结合的BTK的数量与CC-292在体外和自身免疫性疾病的胶原性关节炎模型中的疗效相关。最近，CC-292已经进入人体临床试验，试验设计提供了对安全性、药动学和药效学的快速洞察。这项首例人类健康志愿者试验证明，单次口服2 mg/kg CC-292可以稳定地结合所有循环中的BTK蛋白，为未来临床试验的合理剂量选择提供了依据。这种靶向共价药物设计方法使CC-292的发现和早期临床开发成为可能，并为BTK作为B细胞介导的疾病的有价值的药物靶点提供了支持。
Targeted therapies that suppress B cell receptor (BCR) signaling have emerged as promising agents in autoimmune disease and B cell malignancies. Bruton's tyrosine kinase (Btk) plays a crucial role in B cell development and activation through the BCR signaling pathway and represents a new target for diseases characterized by inappropriate B cell activity. N-(3-(5-fluoro-2-(4-(2-methoxyethoxy)phenylamino)pyrimidin-4-ylamino)phenyl) acrylamide (CC-292) is a highly selective, covalent Btk inhibitor and a sensitive and quantitative assay that measures CC-292-Btk engagement has been developed. This translational pharmacodynamic assay has accompanied CC-292 through each step of drug discovery and development. These studies demonstrate the quantity of Btk bound by CC-292 correlates with the efficacy of CC-292 in vitro and in the collagen-induced arthritis model of autoimmune disease. Recently, CC-292 has entered human clinical trials with a trial design that has provided rapid insight into safety, pharmacokinetics, and pharmacodynamics. This first-in-human healthy volunteer trial has demonstrated that a single oral dose of 2 mg/kg CC-292 consistently engaged all circulating Btk protein and provides the basis for rational dose selection in future clinical trials. This targeted covalent drug design approach has enabled the discovery and early clinical development of CC-292 and has provided support for Btk as a valuable drug target for B-cell mediated disorders.