Department of Medicine, New York Medical College and Westchester Medical Center, Valhalla, NY, 10595, USA.
Biomark Res. 2013 Jan 16;1(1):5. doi: 10.1186/2050-7771-1-5.
JAK-STAT (Janus associated kinase-signal transducer and activator of transcription) pathway plays a critical role in transduction of extracellular signals from cytokines and growth factors involved in hematopoiesis, immune regulation, fertility, lactation, growth and embryogenesis. JAK family contains four cytoplasmic tyrosine kinases, JAK1-3 and Tyk2. Seven STAT proteins have been identified in human cells, STAT1-6, including STAT5a and STAT5b. Negative regulators of JAK-STAT pathways include tyrosine phosphatases (SHP1 and 2, CD45), protein inhibitors of activated STATs (PIAS), suppressors of cytokine signaling (SOCS) proteins, and cytokine-inducible SH2-containing protein (CIS). Dysregulation of JAK-STAT pathway have been found to be key events in a variety of hematological malignancies. JAK inhibitors are among the first successful agents reaching clinical application. Ruxolitinib (Jakafi), a non-selective inhibitor of JAK1 & 2, has been approved by FDA for patients with intermediate to high risk primary or secondary myelofibrosis. This review will also summarize early data on selective JAK inhibitors, including SAR302503 (TG101348), lestaurtinib (CEP701), CYT387, SB1518 (pacritinib), LY2784544, XL019, BMS-911543, NS-018, and AZD1480.
JAK-STAT（Janus 相关激酶-信号转导子和转录激活子）途径在细胞因子和生长因子参与造血、免疫调节、生育、哺乳、生长和胚胎发生的细胞外信号转导中起着关键作用。JAK 家族包含四个细胞质酪氨酸激酶，JAK1-3 和 Tyk2。在人类细胞中已经鉴定出七种 STAT 蛋白，STAT1-6，包括 STAT5a 和 STAT5b。JAK-STAT 途径的负调节剂包括酪氨酸磷酸酶（SHP1 和 2、CD45）、激活 STAT 的蛋白抑制剂（PIAS）、细胞因子信号转导抑制剂（SOCS）蛋白和细胞因子诱导的 SH2 结构域蛋白（CIS）。JAK-STAT 途径的失调已被发现是各种血液恶性肿瘤的关键事件。JAK 抑制剂是最早成功进入临床应用的药物之一。Ruxolitinib（Jakafi），一种非选择性 JAK1 和 JAK2 抑制剂，已被 FDA 批准用于中高危原发性或继发性骨髓纤维化患者。本综述还将总结选择性 JAK 抑制剂的早期数据，包括 SAR302503（TG101348）、lestaurtinib（CEP701）、CYT387、SB1518（pacritinib）、LY2784544、XL019、BMS-911543、NS-018 和 AZD1480。
