文章：

JAK2V617F小分子酪氨酸激酶抑制剂LY2784544的发现与表征

Discovery and characterization of LY2784544, a small-molecule tyrosine kinase inhibitor of JAK2V617F

原文发布日期：2013-04-12

DOI: 10.1038/bcj.2013.6

类型: Original Article

开放获取: 是

英文摘要：

Owing to the prevalence of the JAK2V617F mutation in myeloproliferative neoplasms (MPNs), its constitutive activity, and ability to recapitulate the MPN phenotype in mouse models, JAK2V617F kinase is an attractive therapeutic target. We report the discovery and initial characterization of the orally bioavailable imidazopyridazine, LY2784544, a potent, selective and ATP-competitive inhibitor of janus kinase 2 (JAK2) tyrosine kinase. LY2784544 was discovered and characterized using a JAK2-inhibition screening assay in tandem with biochemical and cell-based assays. LY2784544 in vitro selectivity for JAK2 was found to be equal or superior to known JAK2 inhibitors. Further studies showed that LY2784544 effectively inhibited JAK2V617F-driven signaling and cell proliferation in Ba/F3 cells (IC50=20 and 55 nM, respectively). In comparison, LY2784544 was much less potent at inhibiting interleukin-3-stimulated wild-type JAK2-mediated signaling and cell proliferation (IC50=1183 and 1309 nM, respectively). In vivo, LY2784544 effectively inhibited STAT5 phosphorylation in Ba/F3-JAK2V617F-GFP (green fluorescent protein) ascitic tumor cells (TED50=12.7 mg/kg) and significantly reduced (P<0.05) Ba/F3-JAK2V617F-GFP tumor burden in the JAK2V617F-induced MPN model (TED50=13.7 mg/kg, twice daily). In contrast, LY2784544 showed no effect on erythroid progenitors, reticulocytes or platelets. These data suggest that LY2784544 has potential for development as a targeted agent against JAK2V617F and may have properties that allow suppression of JAK2V617F-induced MPN pathogenesis while minimizing effects on hematopoietic progenitor cells.

摘要翻译： 

由于JAK2V617F突变在骨髓增殖性肿瘤（MPN）中的普遍性、其构成性活性以及在小鼠模型中重现MPN表型的能力，JAK2V617F激酶成为一个有吸引力的治疗靶点。本文报道了口服生物可利用的咪唑吡哒嗪类化合物LY2784544的发现及其初步特征，该化合物是一种强效、选择性且ATP竞争性的Janus激酶2（JAK2）酪氨酸激酶抑制剂。LY2784544是通过JAK2抑制筛选试验结合生化和细胞实验发现并表征的。LY2784544在体外对JAK2的选择性等于或优于已知的JAK2抑制剂。进一步研究表明，LY2784544有效抑制了Ba/F3细胞中JAK2V617F驱动的信号传导和细胞增殖（IC50分别为20 nM和55 nM）。相比之下，LY2784544抑制白细胞介素-3刺激的野生型JAK2介导的信号传导和细胞增殖的效力要低得多（IC50分别为1183 nM和1309 nM）。在体内，LY2784544有效抑制了Ba/F3-JAK2V617F-GFP腹水肿瘤细胞中STAT5的磷酸化（TED50=12.7 mg/kg），并在JAK2V617F诱导的MPN模型中显著降低了（P<0.05）Ba/F3-JAK2V617F-GFP肿瘤负荷（TED50=13.7 mg/kg，每日两次）。相比之下，LY2784544对红系祖细胞、网织红细胞或血小板没有影响。这些数据表明，LY2784544有潜力开发为针对JAK2V617F的靶向药物，并且可能具有抑制JAK2V617F诱导的MPN发病机制同时最小化对造血祖细胞影响的特性。

原文链接：

Discovery and characterization of LY2784544, a small-molecule tyrosine kinase inhibitor of JAK2V617F