JAK2抑制剂治疗骨髓增殖性肿瘤研究进展  

Advances in JAK2 inhibitors for treatment of myeloproliferative neoplasms

作　　者：胡敏[1] 史高娜 石建功[1] 张天泰[1] HU Min;SHI Gao-na;SHI Jian-gong;ZHANG Tian-tai(Institute of Materia Medica,Chinese Academy of Medical Sciences and Peking Union Medical College,Beijing 100050,China)

机构地区：[1]中国医学科学院北京协和医学院药物研究所

出　　处：《药学学报》2019年第6期971-977,共7页Acta Pharmaceutica Sinica

基　　金：国家自然科学基金资助项目(81573445);北京市自然科学基金资助项目(7182115);国家新药创制重大专项资助项目(2018ZX09711001-003-001);中国医学科学院医学与健康科技创新工程项目(2017-I2M-3-011)

摘　　要：骨髓增殖性肿瘤(myelopro1iferative neoplasms,MPNs)是一类造血干细胞异常增生性疾病,主要表现为骨髓中一系或多系细胞出现异常增殖。JAK2磷酸化导致的JAK-STAT信号通路持续活化是诱发MPNs的重要原因,而JAK2激酶的突变可以使其处于持续的磷酸化状态,JAK2最典型的突变是假激酶区V617F的位点突变。95%的红细胞增多症(PV)以及50%的原发性骨髓纤维化(PMF)、血小板增多症(ET)患者中存在这种突变。现已明确JAK2是治疗MPNs的重要靶标,通过抑制JAK2-STAT信号通路的异常激活来治疗MPNs已成为热门研究方向。本文拟从JAK2激酶的生物学功能、JAK2与MPNs的关系以及JAK2小分子抑制剂的研发现状等角度,综述近年来JAK2抑制剂在治疗MPNs疾病的研究进展。Myeloproliferative neoplasms(MPNs)result from clonal expansion of haematopoietic stem cells and are characterized by abnormal proliferation of myeloid lineage cells in the bone marrow.Sustained activation of JAK-STAT signaling pathway due to JAK2 phosphorylation is an important cause of MPNs,and mutation of JAK2 kinase can keep it in a state of continuous phosphorylation.The most typical mutation in JAK2 is a site mutation of V617 F in the pseudokinase domain.The JAK2 V617 F-activating mutation is highly prevalent in MPNs,with frequencies estimated at approximately 95%in polycythaemia vera(PV)and 50%in primary myelofibrosis(PMF)and essential thrombocytosis(ET)patients.It is now clear that JAK2 is an important target for treatment of MPNs.Inhibiting aberrant activation of the JAK2-STAT signaling pathway has become a popular trend in research for effective treatment of MPNs.This review summarizes the research progress in developing JAK2 inhibitors for treatment of MPNs in recent years,including the new discoveries of the biological functions of JAK2,the relationship between JAK2 and MPN,and the status of development of JAK2 small molecule inhibitors.

关 键 词：JAK2激酶 JAK2抑制剂 骨髓增殖性肿瘤 JAK-STAT信号通路 

分 类 号：R967[医药卫生—药理学]