Acalabrutinib (ACP-196): A Covalent Bruton Tyrosine Kinase Inhibitor with a Differentiated Selectivity and In Vivo Potency Profile
Acalabrutinib (ACP-196): A Covalent Bruton Tyrosine Kinase Inhibitor with a Differentiated Selectivity and In Vivo Potency Profile
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DOI：
10.1124/jpet.117.242909
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发表时间：
2017-11-01
影响因子：
3.5
通讯作者：
Kaptein, Allard
中科院分区：
文献类型：
--
作者：
Barf, Tjeerd;Covey, Todd;Kaptein, Allard
几种小分子布鲁顿酪氨酸激酶（BTK）抑制剂正在开发用于B细胞恶性肿瘤和自身免疫性疾病，每种抑制剂的特征在于不同的效力和选择性模式。在此，我们描述了BTK抑制剂acalabrutinib [化合物1，ACP-196（4-[8-氨基-3-[（2S）-1-丁-2-炔酰基吡咯烷-2-基]咪唑并[1，5-a]吡嗪-1-基]-N-（2-吡啶基）苯甲酰胺）]的药理学表征。Acalabrutinib具有与BTK中的Cys 481共价结合的反应性丁酰胺基团。相对于本文所述的其他BTK抑制剂，acalabrutinib的固有反应性降低有助于限制对具有半胱氨酸介导的共价结合潜力的脱靶激酶的抑制。Acalabrutinib表现出比伊曲替尼和斯培替尼（分别为化合物2和3）更高的生物化学和细胞选择性。重要的是，脱靶激酶，如表皮生长因子受体（EGFR）和白细胞介素2诱导的T细胞激酶（ITK），没有受到抑制。在人外周血单核细胞和全血中测定抗免疫球蛋白M诱导的CD 69表达的抑制潜力，证明acalabrutinib是一种有效的功能性BTK抑制剂。小鼠体内评价显示，acalabrutinib比伊曲替尼和司匹替尼更有效。临床前和临床研究表明，BTK占用的水平和持续时间与体内功效相关。在健康成人志愿者中对acalabrutinib的药代动力学特性进行的评价表明，吸收迅速，消除迅速。在这些健康个体中，100 mg单次口服剂量在3和12小时显示约99%的中位靶向覆盖率，在24小时显示约90%的外周B细胞中位靶向覆盖率。总之，acalabrutinib是一种BTK抑制剂，与伊曲替尼和司匹替尼相比具有关键药理学差异，目前正在临床试验中进行评价。
Several small-molecule Bruton tyrosine kinase (BTK) inhibitors are in development for B cell malignancies and autoimmune disorders, each characterized by distinct potency and selectivity patterns. Herein we describe the pharmacologic characterization of BTK inhibitor acalabrutinib [compound 1, ACP-196 (4-[8-amino-3-[(2S)-1-but-2-ynoylpyrrolidin-2-yl] imidazo[1,5-a] pyrazin-1-yl]-N-(2-pyridyl) benzamide)]. Acalabrutinib possesses a reactive butynamide group that binds covalently to Cys481 in BTK. Relative to the other BTK inhibitors described here, the reduced intrinsic reactivity of acalabrutinib helps to limit inhibition of off-target kinases having cysteine-mediated covalent binding potential. Acalabrutinib demonstrated higher biochemical and cellular selectivity than ibrutinib and spebrutinib (compounds 2 and 3, respectively). Importantly, off-target kinases, such as epidermal growth factor receptor (EGFR) and interleukin 2-inducible T cell kinase (ITK), were not inhibited. Determination of the inhibitory potential of anti-immunoglobulin M-induced CD69 expression in human peripheral blood mononuclear cells and whole blood demonstrated that acalabrutinib is a potent functional BTK inhibitor. In vivo evaluation in mice revealed that acalabrutinib is more potent than ibrutinib and spebrutinib. Preclinical and clinical studies showed that the level and duration of BTK occupancy correlates with in vivo efficacy. Evaluation of the pharmacokinetic properties of acalabrutinib in healthy adult volunteers demonstrated rapid absorption and fast elimination. In these healthy individuals, a single oral dose of 100 mg showed approximately 99% median target coverage at 3 and 12 hours and around 90% at 24 hours in peripheral B cells. In conclusion, acalabrutinib is a BTK inhibitor with key pharmacologic differentiators versus ibrutinib and spebrutinib and is currently being evaluated in clinical trials.