Genentech Inc. , 1 DNA Way, South San Francisco, California 94080, United States.
J Med Chem. 2014 Jul 10;57(13):5714-27. doi: 10.1021/jm500550e. Epub 2014 Jun 27.
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.
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 细胞信号转导中发挥主要作用，人们已经投入大量精力来发现 ITK 选择性抑制剂，作为治疗哮喘等炎症性疾病的潜在药物。本研究以先前公开的吲唑系列抑制剂为起点，利用 X 射线晶体学和溶解度预测指数（SFI）作为指导，对一系列四氢吲唑抑制剂进行了进化，提高了其效力、选择性和药物性质。本研究的重点包括确定配体上方的选择性口袋，并确定适当的亲脂性取代基来占据这个空间。这一努力最终确定了一种有效的、选择性的 ITK 抑制剂（GNE-9822），其在临床前物种中具有良好的 ADME 特性。
