Potent and Selective Inhibition of Polycythemia by the Quinoxaline JAK2 Inhibitor NVP-BSK805
Potent and Selective Inhibition of Polycythemia by the Quinoxaline JAK2 Inhibitor NVP-BSK805
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DOI：
10.1158/1535-7163.mct-10-0053
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发表时间：
2010-07-01
影响因子：
5.7
通讯作者：
Radimerski, Thomas
中科院分区：
文献类型：
--
作者：
Baffert, Fabienne;Regnier, Catherine H.;Radimerski, Thomas
最近在JAK2中发现了一个获得性激活点突变，将氨基酸位置617的缬氨酸替换为苯丙氨酸，这极大地提高了我们对慢性骨髓增殖性肿瘤分子机制的理解。引人注目的是，JAK2（V617F）突变几乎在所有真性红细胞增多症患者中发现，大约每2名原发性血小板增多症和原发性骨髓纤维化患者中发现JAK2（V617F）突变。因此，JAK2代表了治疗骨髓增殖性肿瘤的一个有希望的靶点，并且正在进行大量的努力来发现和开发该激酶的抑制剂。在这里，我们报道了一种新型替代喹诺啉NVP-BSK805对JAK2（V617F）和JAK2野生型酶的有效抑制作用，该酶以atp竞争方式起作用。在JAK家族中，NVP-BSK805在体外对JAK2具有20倍以上的选择性，并且在更广泛的激酶谱分析中具有出色的选择性。该化合物在携带JAK2（V617F）的细胞中减弱STAT5的组成磷酸化，同时抑制细胞增殖和诱导凋亡。在体内，NVP-BSK805具有良好的口服生物利用度和较长的半衰期。在Ba/F3 JAK2（V617F）细胞驱动的小鼠机制模型中，该抑制剂有效抑制白血病细胞扩散和脾肿大。此外，NVP-BSK805在小鼠和大鼠中有效抑制重组人促红细胞生成素诱导的红细胞增多症和髓外红细胞生成。巨蟹座；9 (7);1945 - 55。(c) 2010年aacr。
The recent discovery of an acquired activating point mutation in JAK2, substituting valine at amino acid position 617 for phenylalanine, has greatly improved our understanding of the molecular mechanism underlying chronic myeloproliferative neoplasms. Strikingly, the JAK2(V617F) mutation is found in nearly all patients suffering from polycythemia vera and in roughly every second patient suffering from essential thrombocythemia and primary myelofibrosis. Thus, JAK2 represents a promising target for the treatment of myeloproliferative neoplasms and considerable efforts are ongoing to discover and develop inhibitors of the kinase. Here, we report potent inhibition of JAK2(V617F) and JAK2 wild-type enzymes by a novel substituted quinoxaline, NVP-BSK805, which acts in an ATP-competitive manner. Within the JAK family, NVP-BSK805 displays more than 20-fold selectivity towards JAK2 in vitro, as well as excellent selectivity in broader kinase profiling. The compound blunts constitutive STAT5 phosphorylation in JAK2(V617F)-bearing cells, with concomitant suppression of cell proliferation and induction of apoptosis. In vivo, NVP-BSK805 exhibited good oral bioavailability and a long half-life. The inhibitor was efficacious in suppressing leukemic cell spreading and splenomegaly in a Ba/F3 JAK2(V617F) cell-driven mouse mechanistic model. Furthermore, NVP-BSK805 potently suppressed recombinant human erythropoietin-induced polycythemia and extramedullary erythropoiesis in mice and rats. Mol Cancer Ther; 9(7); 1945-55. (C) 2010 AACR.