School of Science, China Pharmaceutical University, Nanjing, China.
Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China.
Bioorg Med Chem. 2019 Apr 15;27(8):1562-1576. doi: 10.1016/j.bmc.2019.02.054. Epub 2019 Feb 28.
Janus kinases (JAKs) regulate various cancers and immune responses and are targets for the treatment of cancers and immune diseases. A new series of 1H-pyrazolo[3,4-d]pyrimidin-4-amino derivatives were synthesized and optimized by introducing a functional 3,5-disubstituted-1H-pyrazole moiety into the C-3 moiety of pyrazole template, and then were biologically evaluated as potent Janus kinase 2 (JAK2) inhibitors. Among these molecules, inhibitors 11f, 11g, 11h and 11k displayed strong activity and selectivity against the JAK2 kinase, with IC values of 7.2 nM, 6.5 nM, 8.0 nM and 9.7 nM, respectively. In particular, the cellular inhibitory assay and western blot analysis further support the JAK2 selectivity of compound 11g also in cells. Furthermore, compound 11g also exhibited potent inhibitory activity in lymphocytes proliferation assay and delayed hypersensitivity assay. Taken together, the novel JAK2 selective inhibitors discovered in this study may be potential lead compounds for new drug discovery via further development of more potent and selective JAK2 inhibitors.
Janus 激酶（JAKs）调节各种癌症和免疫反应，是治疗癌症和免疫疾病的靶点。我们通过将功能化的 3,5-二取代 1H-吡唑并[3,4-d]嘧啶-4-氨基片段引入吡唑模板的 C-3 部分，合成了一系列新的 1H-吡唑并[3,4-d]嘧啶-4-氨基衍生物，并对其进行了优化，将其作为有效的 Janus 激酶 2（JAK2）抑制剂进行了生物学评价。在这些分子中，抑制剂 11f、11g、11h 和 11k 对 JAK2 激酶表现出很强的活性和选择性，IC 值分别为 7.2 nM、6.5 nM、8.0 nM 和 9.7 nM。特别是细胞抑制试验和 Western blot 分析进一步支持化合物 11g 在细胞中也具有 JAK2 选择性。此外，化合物 11g 在淋巴细胞增殖试验和迟发型超敏反应试验中也表现出很强的抑制活性。总之，本研究中发现的新型 JAK2 选择性抑制剂可能是通过进一步开发更有效和选择性的 JAK2 抑制剂来发现新药的潜在先导化合物。
