CYT387, a novel JAK2 inhibitor, induces hematologic responses and normalizes inflammatory cytokines in murine myeloproliferative neoplasms
CYT387, a novel JAK2 inhibitor, induces hematologic responses and normalizes inflammatory cytokines in murine myeloproliferative neoplasms
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DOI：
10.1182/blood-2009-05-223727
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发表时间：
2010-06-24
期刊：
影响因子：
20.3
通讯作者：
Deininger, Michael W.
中科院分区：
文献类型：
--
作者：
Tyner, Jeffrey W.;Bumm, Thomas G.;Deininger, Michael W.
Janus激酶2（JAK 2）的激活等位基因（如JAK 2 V617 F）是骨髓增生性肿瘤（MPN）发病机制的核心，这表明靶向JAK 2的小分子抑制剂可能在治疗上有用。我们已经确定了氨基嘧啶衍生物（CYT 387），抑制JAK 1，JAK 2和酪氨酸激酶2（TYK 2）在低纳摩尔浓度，很少有额外的目标。在0.5和1.5 μ M之间CYT 387引起JAK 2依赖性造血细胞系的生长抑制和凋亡，而非造血细胞系不受影响。在鼠MPN模型中，CYT 387使白色细胞计数、血细胞比容、脾脏大小正常化，并恢复炎性细胞因子的生理水平。尽管血液学反应和JAK 2 V617 F等位基因负荷减少，但JAK 2 V617 F细胞持续存在，并且在停止治疗后MPN复发，这表明JAK 2抑制剂可能无法消除JAK 2 V617 F细胞，这与JAK 2抑制剂在骨髓纤维化中的临床试验的初步结果一致。虽然JAK 2抑制剂的临床益处可能是实质性的，但这不仅仅是由于炎性细胞因子的减少和症状的改善，我们的数据增加了越来越多的证据，即激酶抑制剂单一疗法治疗恶性疾病是无效的，这表明需要药物组合以最佳地靶向恶性细胞。血(2010; 115（25）：5232-5240）
Activating alleles of Janus kinase 2 (JAK2) such as JAK2V617F are central to the pathogenesis of myeloproliferative neoplasms (MPN), suggesting that small molecule inhibitors targeting JAK2 may be therapeutically useful. We have identified an aminopyrimidine derivative (CYT387), which inhibits JAK1, JAK2, and tyrosine kinase 2 (TYK2) at low nanomolar concentrations, with few additional targets. Between 0.5 and 1.5 mu M CYT387 caused growth suppression and apoptosis in JAK2-dependent hematopoietic cell lines, while nonhematopoietic cell lines were unaffected. In a murine MPN model, CYT387 normalized white cell counts, hematocrit, spleen size, and restored physiologic levels of inflammatory cytokines. Despite the hematologic responses and reduction of the JAK2V617F allele burden, JAK2V617F cells persisted and MPN recurred upon cessation of treatment, suggesting that JAK2 inhibitors may be unable to eliminate JAK2V617F cells, consistent with preliminary results from clinical trials of JAK2 inhibitors in myelofibrosis. While the clinical benefit of JAK2 inhibitors may be substantial, not the least due to reduction of inflammatory cytokines and symptomatic improvement, our data add to increasing evidence that kinase inhibitor monotherapy of malignant disease is not curative, suggesting a need for drug combinations to optimally target the malignant cells. Blood. (2010; 115(25):5232-5240)