College of Science, China Pharmaceutical University, Nanjing, PR China.
Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, PR China.
Bioorg Med Chem. 2019 Apr 15;27(8):1646-1657. doi: 10.1016/j.bmc.2019.03.009. Epub 2019 Mar 5.
Janus kinases (JAKs) play a key role in the proliferation, apoptosis and differentiation of immune cells, and JAKs are considered as an attractive target for the treatment of inflammatory and autoimmune diseases. Here we show the design and optimization of pyrimidine-4,6-diamine derivatives as selectivity JAK3 inhibitors. Compound 11e, which might interact with unique cysteine (Cys909) residue in JAK3, exhibited excellent JAK3 inhibitory activity (IC = 2.1 nM) and high JAK kinase selectivity. In cellular assay, 11e showed moderate potency inhibiting IL-2-stimulated T cell proliferation. The data supports the further development of novel JAKs inhibitors.
Janus 激酶（JAKs）在免疫细胞的增殖、凋亡和分化中发挥着关键作用，因此 JAKs 被认为是治疗炎症性和自身免疫性疾病的有吸引力的靶点。在这里，我们展示了嘧啶-4,6-二胺衍生物作为选择性 JAK3 抑制剂的设计和优化。化合物 11e 可能与 JAK3 中的独特半胱氨酸（Cys909）残基相互作用，表现出优异的 JAK3 抑制活性（IC=2.1nM）和高 JAK 激酶选择性。在细胞测定中，11e 显示出适度的抑制 IL-2 刺激的 T 细胞增殖的活性。这些数据支持进一步开发新型 JAK 抑制剂。
