NSC114792, a novel small molecule identified through structure-based computational database screening, selectively inhibits JAK3
NSC114792, a novel small molecule identified through structure-based computational database screening, selectively inhibits JAK3
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DOI：
10.1186/1476-4598-9-36
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发表时间：
2010-02-11
期刊：
影响因子：
37.3
通讯作者：
Baeg, Gyeong-Hun
中科院分区：
文献类型：
--
作者：
Kim, Byung-Hak;Jee, Jun-Goo;Baeg, Gyeong-Hun
背景：缺乏JAK3或共同的伽马链(Gamma C)表达的人或动物表现出严重的联合免疫缺乏病，表明JAK3在T细胞发育和免疫系统的动态平衡中起着至关重要的作用。JAK3也被认为与肿瘤的发生机制有关。最近的研究发现，在包括急性巨核细胞白血病在内的各种血液系统恶性肿瘤患者中，JAK3基因突变处于激活状态。重要的是，对其中一些JAK3突变的功能分析已经被证明在动物模型中导致致命的血液系统恶性肿瘤。这些观察结果使JAK3成为治疗各种人类疾病的理想靶点。为了寻找新的JAK3小分子抑制剂，我们利用JAK3激酶域的三维结构和化合物的NCI多样性集进行了基于结构的虚拟筛选。结果：我们鉴定NSC114792为先导化合物。该化合物在体外可直接阻断JAK3的催化活性，但不能阻断JAK家族其他成员的催化活性。此外，用该化合物处理32D/IL-2Rβ细胞，可阻断依赖IL-2的JAK3/STAT5的激活，但不阻断依赖IL-3的JAK2/STAT5的激活。与NSC114792对JAK3的特异性一致，它选择性地抑制持续激活的JAK3，但不影响其他JAK家族成员的活性和各种癌细胞系中其他致癌蛋白的活性。结论：NSC114792是一种选择性抑制JAK3活性的先导化合物。因此，我们的研究表明，JAK3的这种小分子抑制剂可以作为开发一类针对JAK3活性的新药物的起点，并可能对由JAK3活性异常引起的各种疾病具有治疗潜力。
Background: Human or animals lacking either JAK3 or the common gamma chain (gamma c) expression display severe combined immunodeficiency disease, indicating the crucial role of JAK3 in T-cell development and the homeostasis of the immune system. JAK3 has also been suggested to contribute to the pathogenesis of tumorigenesis. Recent studies identified activating JAK3 mutations in patients with various hematopoietic malignancies, including acute megakaryoblastic leukemia. Importantly, functional analyses of some of those JAK3 mutations have been shown to cause lethal hematopoietic malignancies in animal models. These observations make JAK3 an ideal therapeutic target for the treatment of various human diseases. To identify novel small molecule inhibitors of JAK3, we performed structure-based virtual screen using the 3D structure of JAK3 kinase domain and the NCI diversity set of compounds.Results: We identified NSC114792 as a lead compound. This compound directly blocked the catalytic activity of JAK3 but not that of other JAK family members in vitro. In addition, treatment of 32D/IL-2R beta cells with the compound led to a block in IL-2-dependent activation of JAK3/STAT5 but not IL-3-dependent activation of JAK2/STAT5. Consistent with the specificity of NSC114792 for JAK3, it selectively inhibited persistently-activated JAK3, but failed to affect the activity of other JAK family members and other oncogenic kinases in various cancer cell lines. Finally, we showed that NSC114792 decreases cell viability by inducing apoptosis through down-regulating antiapoptotic gene expression only in cancer cells harboring persistently-active JAK3.Conclusions: NSC114792 is a lead compound that selectively inhibits JAK3 activity. Therefore, our study suggests that this small molecule inhibitor of JAK3 can be used as a starting point to develop a new class of drugs targeting JAK3 activity, and may have therapeutic potential in various diseases that are caused by aberrant JAK3 activity.