Department of Hematology, Medical University of Lodz and Copernicus Memorial Hospital, 93-510 Lodz, Ciolkowskiego 2, Poland.
Curr Med Chem. 2013;20(9):1147-61. doi: 10.2174/0929867311320090004.
The Janus family kinases (JAKs), JAK1, JAK2, JAK3, and TYK2, are involved in cell growth, survival, development, and differentiation of a variety of cells, particularly immune cells and hematopoietic cells. They form a subgroup of the non-receptor protein tyrosine kinases. Activating mutations within each of the JAKs is associated with malignant transformations; the most common are mutations of JAK2 in polycythemia vera (PV) and other myeloproliferative neoplasms (MPN). Identification of the V617F mutation of the JAK2 gene (JAK2 V617F) led to an important breakthrough in the understanding of MPN disease pathogenesis. The JAK2 V617F mutation is present in the majority of PV patients, and about 50% of patients with essential thrombocythemia (ET) and primary myelofibrosis (PMF) are affected. This mutation leads to hyperactivation of JAK2, cytokine-independent signaling, and subsequent activation of downstream signaling networks. JAK2 ATP-competitive inhibitors that indirectly inhibit the JAK-STAT pathway are new candidates for the treatment of MPN. JAK2 inhibitors in development for the treatment of MPN have demonstrated clinical activity with minimal toxicity. These agents consistently alleviate constitutional symptoms and reduce spleen size in PMF and other MPN. However, some of these inhibitors have additional unique effects. Ruxolitinib causes a significant reduction in the level of pro-inflammatory cytokines. Another inhibitor, CYT387, improves anemia. Many other JAK2 inhibitors such as TG101348 or SAR302503, SB1518, CEP701 and LY2784544 are now under investigation for MPN development. In contrast tasocitinib, a predominantly JAK3 inhibitor, is being evaluated in a number of inflammatory and immunological diseases, including rheumatoid arthritis, psoriasis, ulcerative colitis, dry eye disease and in kidney transplant patients. In conclusion the use of JAK inhibitors in MPN and some of the immune-mediated disorders is a promising new strategy for therapy. However, definitive data from ongoing and future preclinical and clinical trials will aid in better defining the status of these drugs in the treatment of these diseases.
该 Janus 家族激酶（JAKs），JAK1，JAK2，JAK3 和 TYK2，参与细胞生长，存活，发展和分化的各种细胞，特别是免疫细胞和造血细胞。他们形成的非受体蛋白酪氨酸激酶的亚群。激活突变内的每个 JAKs 是与恶性转化相关联的;最常见的是在真性红细胞增多症（PV）和其他骨髓增生性肿瘤（MPN）JAK2 的突变。鉴定 JAK2 基因的 V617F 突变（JAK2 V617F）导致在理解 MPN 疾病发病机制的一个重要突破。JAK2 V617F 突变存在于大多数 PV 患者中，并且约 50％的特发性血小板增多症（ET）和原发性骨髓纤维化（PMF）患者受影响。这种突变导致 JAK2 的过度激活，细胞因子独立的信号转导，以及随后的下游信号转导网络的激活。JAK2ATP 竞争性抑制剂，间接抑制 JAK-STAT 途径是治疗 MPN 的新候选者。在 MPN 治疗中开发的 JAK2 抑制剂具有最小毒性的临床活性。这些药物一致地缓解体质症状并减少 PMF 和其他 MPN 中的脾脏大小。然而，一些这些抑制剂具有另外的独特的效果。鲁索利替尼导致促炎细胞因子水平的显著降低。另一种抑制剂，CYT387，改善贫血。许多其他 JAK2 抑制剂，如 TG101348 或 SAR302503、SB1518、CEP701 和 LY2784544，现在正在为 MPN 的发展而进行研究。相比之下，主要的 JAK3 抑制剂 tasocitinib，正在评估在许多炎症和自身免疫性疾病，包括类风湿关节炎，银屑病，溃疡性结肠炎，干眼病和肾移植患者。总之，在 MPN 和一些免疫介导的疾病中使用 JAK 抑制剂是治疗的一种有前途的新策略。然而，来自正在进行和未来的临床前和临床试验的明确数据将有助于更好地定义这些药物在治疗这些疾病中的地位。
