Property- and Structure-Guided Discovery of a Tetrahydroindazole Series of Interleukin-2 Inducible T-Cell Kinase Inhibitors
Property- and Structure-Guided Discovery of a Tetrahydroindazole Series of Interleukin-2 Inducible T-Cell Kinase Inhibitors
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DOI：
10.1021/jm500550e
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发表时间：
2014-07-10
影响因子：
7.3
通讯作者：
Pei, Zhonghua
中科院分区：
文献类型：
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作者：
Burch, Jason D.;Lau, Kevin;Pei, Zhonghua
白细胞介素-2诱导的T细胞激酶（ITK）是酪氨酸激酶Tec家族的成员，在T细胞受体（TCR）下游的T细胞信号传导中起主要作用，并且已经进行了相当大的努力来发现ITK选择性抑制剂作为炎性疾病如哮喘的潜在治疗。使用先前公开的吲唑系列抑制剂作为起点，并使用X射线晶体学和溶解度预测指数（SFI）作为指导，我们开发了一系列具有改善的效力、选择性和药物性质的四氢吲唑抑制剂。亮点包括识别的选择性口袋上面的配体平面，并确定适当的亲脂性取代基占据这个空间。这一努力最终确定了一种有效的和选择性的ITK抑制剂（GNE-9822），在临床前物种中具有良好的ADME特性。
Interleukin-2 inducible T-cell kinase (ITK), a member of the Tec family of tyrosine kinases, plays a major role in T-cell signaling downstream of the T-cell receptor (TCR), and considerable efforts have been directed toward discovery of ITK-selective inhibitors as potential treatments of inflammatory disorders such as asthma. Using a previously disclosed indazole series of inhibitors as a starting point, and using X-ray crystallography and solubility forecast index (SFI) as guides, we evolved a series of tetrahydroindazole inhibitors with improved potency, selectivity, and pharmaceutical properties. Highlights include identification of a selectivity pocket above the ligand plane, and identification of appropriate lipophilic substituents to occupy this space. This effort culminated in identification of a potent and selective ITK inhibitor (GNE-9822) with good ADME properties in preclinical species.