Research and Development, Bristol-Myers Squibb, Princeton, NJ 08543-4000, USA.
Leukemia. 2012 Feb;26(2):280-8. doi: 10.1038/leu.2011.292. Epub 2011 Oct 21.
We report the characterization of BMS-911543, a potent and selective small-molecule inhibitor of the Janus kinase (JAK) family member, JAK2. Functionally, BMS-911543 displayed potent anti-proliferative and pharmacodynamic (PD) effects in cell lines dependent upon JAK2 signaling, and had little activity in cell types dependent upon other pathways, such as JAK1 and JAK3. BMS-911543 also displayed anti-proliferative responses in colony growth assays using primary progenitor cells isolated from patients with JAK2(V617F)-positive myeloproliferative neoplasms (MPNs). Similar to these in vitro observations, BMS-911543 was also highly active in in vivo models of JAK2 signaling, with sustained pathway suppression being observed after a single oral dose. At low dose levels active in JAK2-dependent PD models, no effects were observed in an in vivo model of immunosuppression monitoring antigen-induced IgG and IgM production. Expression profiling of JAK2(V617F)-expressing cells treated with diverse JAK2 inhibitors revealed a shared set of transcriptional changes underlying pharmacological effects of JAK2 inhibition, including many STAT1-regulated genes and STAT1 itself. Collectively, our results highlight BMS-911543 as a functionally selective JAK2 inhibitor and support the therapeutic rationale for its further characterization in patients with MPN or in other disorders characterized by constitutively active JAK2 signaling.
我们报告了 BMS-911543 的特征，BMS-911543 是一种有效的、选择性的小分子 Janus 激酶（JAK）家族成员 JAK2 抑制剂。在功能上，BMS-911543 在依赖 JAK2 信号的细胞系中显示出强大的抗增殖和药效学（PD）作用，而在依赖其他途径（如 JAK1 和 JAK3）的细胞类型中活性较小。BMS-911543 还在使用从 JAK2(V617F)-阳性骨髓增殖性肿瘤（MPN）患者分离的原代祖细胞进行的集落生长测定中显示出抗增殖反应。与这些体外观察结果相似，BMS-911543 在 JAK2 信号的体内模型中也具有高度活性，在单次口服剂量后观察到持续的途径抑制。在依赖 JAK2 的 PD 模型中，在低剂量水平下有效，在监测抗原诱导 IgG 和 IgM 产生的体内免疫抑制模型中未观察到任何作用。用不同的 JAK2 抑制剂处理 JAK2(V617F)-表达细胞的表达谱分析揭示了 JAK2 抑制药理学作用的一组共同的转录变化，包括许多 STAT1 调节基因和 STAT1 本身。总的来说，我们的结果强调了 BMS-911543 是一种功能选择性的 JAK2 抑制剂，并支持其在 MPN 患者或其他以 JAK2 信号持续激活为特征的疾病中进一步表征的治疗原理。
