Structure-based design and synthesis of pyrimidine-4,6-diamine derivatives as Janus kinase 3 inhibitors
Structure-based design and synthesis of pyrimidine-4,6-diamine derivatives as Janus kinase 3 inhibitors
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基于结构的设计和合成嘧啶-4,6-二胺衍生物作为 Janus 激酶 3 抑制剂
DOI：
10.1016/j.bmc.2019.03.009
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发表时间：
2019
影响因子：
3.5
通讯作者：
Zhang Da Yong
中科院分区：
文献类型：
--
作者：
Yu Ru Nan;Chen Cheng Juan;Shu Lei;Yin Yuan;Wang Zhi Jian;Zhang Tian Tai;Zhang Da Yong
Janus激酶（JAK）在免疫细胞的增殖、凋亡和分化中起着关键作用，并且JAK被认为是治疗炎症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JAK 3抑制剂的设计和优化。化合物11 e可能与JAK 3中独特的半胱氨酸（Cys 909）残基相互作用，显示出优异的JAK 3抑制活性（IC 50 = 2.1 nM）和高JAK激酶选择性。在细胞试验中，11个显示出中等的抑制IL-2刺激的T细胞增殖的效力。这些数据支持进一步开发新型JAK抑制剂。
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. Compound11e, which might interact with unique cysteine (Cys909) residue in JAK3, exhibited excellent JAK3 inhibitory activity (IC50= 2.1 nM) and high JAK kinase selectivity. In cellular assay,11eshowed moderate potency inhibiting IL-2-stimulated T cell proliferation. The data supports the further development of novel JAKs inhibitors.