Cephalon, Inc., Drug Discovery Research, 145 Brandywine Parkway, West Chester, PA 19380, USA.
Biochem Pharmacol. 2012 May 1;83(9):1136-45. doi: 10.1016/j.bcp.2011.12.024. Epub 2011 Dec 24.
Janus kinases have proved to be essential for many immunological processes but there is growing evidence that they also play a critical role in pathogenesis of many diseases including inflammatory diseases and cancer where they promote multiple steps of tumorigenesis. Several companies are in late stage clinical programs for the development of JAK kinase inhibitors and the first small molecule JAK inhibitor, Jakafi® (ruxolitinib) has been just approved for treatment of myeloproliferative neoplasms. Several other molecules are on the rise to treat arthritis, psoriasis and multiple types of cancer. This commentary will provide a review of the JAK kinase field as it pertains to small molecule inhibition for the treatment of cancer and autoimmune diseases with an emphasis on JAK2. The use of experimental and clinical inhibitors of JAK will be discussed for solid tumor and hematological malignancies, lupus, arthritis, colitis, neurological disorders, pain, diabetes and cardiovascular disease. In addition, it will review current paradigms in the field and treatment programs which could be complemented by small molecule inhibitors of Janus kinase.
Janus 激酶已被证明对许多免疫过程至关重要，但越来越多的证据表明，它们在许多疾病的发病机制中也起着关键作用，包括炎症性疾病和癌症，在这些疾病中，它们促进了肿瘤发生的多个步骤。几家公司正在进行晚期临床项目，以开发 JAK 激酶抑制剂，第一种小分子 JAK 抑制剂 Jakafi®（ruxolitinib）刚刚获准用于治疗骨髓增生性肿瘤。还有其他几种药物正在兴起，用于治疗关节炎、牛皮癣和多种癌症。本评论将综述小分子抑制 JAK 激酶治疗癌症和自身免疫性疾病的领域，重点介绍 JAK2。将讨论实验和临床抑制剂在实体瘤和血液系统恶性肿瘤、狼疮、关节炎、结肠炎、神经紊乱、疼痛、糖尿病和心血管疾病中的应用。此外，它还将回顾该领域的当前范例和治疗方案，这些方案可以通过 Janus 激酶的小分子抑制剂来补充。
