Department of Pediatrics, Division of Hematology/Oncology, New York Medical College, Valhalla, New York 10595, USA.
Mol Cancer. 2010 Feb 11;9:36. doi: 10.1186/1476-4598-9-36.
Human or animals lacking either JAK3 or the common gamma chain (gammac) 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.
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-2Rbeta 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 anti-apoptotic gene expression only in cancer cells harboring persistently-active JAK3.
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.
缺乏 JAK3 或共同γ链（γc）表达的人类或动物患有严重联合免疫缺陷病，表明 JAK3 在 T 细胞发育和免疫系统稳态中起着至关重要的作用。JAK3 也被认为有助于肿瘤发生的发病机制。最近的研究在包括急性巨核细胞白血病在内的各种血液恶性肿瘤患者中发现了激活的 JAK3 突变。重要的是，一些 JAK3 突变的功能分析已在动物模型中导致致命性血液恶性肿瘤。这些观察结果使 JAK3 成为治疗各种人类疾病的理想治疗靶标。为了鉴定 JAK3 的新型小分子抑制剂，我们使用 JAK3 激酶结构域的 3D 结构和 NCI 多样性化合物集进行了基于结构的虚拟筛选。
我们鉴定出 NSC114792 作为先导化合物。该化合物在体外直接阻断 JAK3 的催化活性，但不阻断其他 JAK 家族成员的活性。此外，用该化合物处理 32D/IL-2Rβ 细胞会导致 JAK3/STAT5 对 IL-2 依赖性激活的阻断，但不会导致 JAK2/STAT5 对 IL-3 的依赖性激活。与 NSC114792 对 JAK3 的特异性一致，它选择性地抑制持续激活的 JAK3，但不能影响各种癌细胞系中其他 JAK 家族成员和其他致癌激酶的活性。最后，我们表明 NSC114792 通过下调抗凋亡基因的表达仅在携带持续激活的 JAK3 的癌细胞中诱导细胞凋亡，从而降低细胞活力。
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，这种 JAK3 的小分子抑制剂可用作开发靶向 JAK3 活性的新药的起点，并且在由异常 JAK3 活性引起的各种疾病中可能具有治疗潜力。
