Kiss Róbert, Polgár Tímea, Kirabo Annet, Sayyah Jacqueline, Figueroa Nicholas C, List Alan F, Sokol Lubomir, Zuckerman Kenneth S, Gali Meghanath, Bisht Kirpal S, Sayeski Peter P, Keseru György M
Department of Pharmaceutical Chemistry, Semmelweis University, 9 Hogyes Endre u., Budapest H-1092, Hungary.
Bioorg Med Chem Lett. 2009 Jul 1;19(13):3598-601. doi: 10.1016/j.bmcl.2009.04.138. Epub 2009 May 5.
Janus kinase 2 (JAK2) plays a crucial role in the pathomechanism of myeloproliferative disorders and hematologic malignancies. A somatic mutation of JAK2 (Val617Phe) was previously shown to occur in 98% of patients with polycythemia vera and 50% of patients with essential thrombocythemia and primary myelofibrosis. Thus, effective JAK2 kinase inhibitors may be of significant therapeutic importance. Here, we applied a structure-based virtual screen to identify novel JAK2 inhibitors. One JAK2 inhibitor in particular, G6, demonstrated remarkable potency as well as specificity, which makes it as a potential lead candidate against diseases related to elevated JAK2 tyrosine kinase activity.
Janus激酶2（JAK2）在骨髓增殖性疾病和血液系统恶性肿瘤的发病机制中起关键作用。先前研究表明，JAK2的体细胞突变（Val617Phe）存在于98%的真性红细胞增多症患者以及50%的原发性血小板增多症和原发性骨髓纤维化患者中。因此，有效的JAK2激酶抑制剂可能具有重要的治疗意义。在此，我们应用基于结构的虚拟筛选来鉴定新型JAK2抑制剂。其中一种JAK2抑制剂G6表现出显著的效力和特异性，使其成为针对与JAK2酪氨酸激酶活性升高相关疾病的潜在先导候选药物。
