Grandage Victoria L, Everington Tamara, Linch David C, Khwaja Asim
Department of Haematology, Royal Free and University College London Medical School, London, UK.
Br J Haematol. 2006 Nov;135(3):303-16. doi: 10.1111/j.1365-2141.2006.06291.x. Epub 2006 Sep 4.
Aberrant activation of Janus kinase/signal transducers and activators of transcription (JAK/STAT) signalling is implicated in a number of haematological malignancies and effective JAK inhibitors may be therapeutically useful. We found that Gö6976, an indolocarbazole inhibitor of the calcium-dependent isozymes of protein kinase C (PKC), inhibited interleukin 3/granulocyte-macrophage colony-stimulating factor-induced signalling, proliferation and survival whereas Gö6983, a broad spectrum PKC inhibitor, had no such effects. Gö6976 was found to be a direct and potent inhibitor of JAK2 in vitro. Gö6976 also inhibited signalling, survival and proliferation in cells expressing the leukaemia-associated TEL-JAK2 fusion protein and the myeloproliferative disorder (MPD)-associated JAK2 V617F mutant. In primary acute myeloid leukaemia (AML) cells, incubation with Gö6976 reduced constitutive STAT activity in all cases studied. In addition, Akt and mitogen-activated protein kinase phosphorylation were reduced in 4/5 FLT3-internal tandem duplication (ITD) positive AML cases and 7/13 FLT3-wild-type (WT) cases. Expression of FLT3-WT, ITD and D835Y in 32D cells showed that Gö6976 is also a potent inhibitor of WT and mutant FLT3. In AML cells, Gö6976 reduced the survival to 55 +/- 5% of control in FLT3-ITD cases and to 69 +/- 5% in FLT3-WT samples. These data may help identify clinically useful compounds based on the structure of Gö6976, which can be employed for the treatment of MPDs as well as AML.
Janus激酶/信号转导子和转录激活子（JAK/STAT）信号通路的异常激活与多种血液系统恶性肿瘤有关，有效的JAK抑制剂可能具有治疗作用。我们发现，蛋白激酶C（PKC）钙依赖性同工酶的吲哚咔唑抑制剂Gö6976可抑制白细胞介素3/粒细胞-巨噬细胞集落刺激因子诱导的信号传导、增殖和存活，而广谱PKC抑制剂Gö6983则无此作用。研究发现，Gö6976在体外是JAK2的直接有效抑制剂。Gö6976还可抑制表达白血病相关TEL-JAK2融合蛋白和骨髓增殖性疾病（MPD）相关JAK2 V617F突变体的细胞中的信号传导、存活和增殖。在原发性急性髓系白血病（AML）细胞中，与Gö6976孵育在所有研究病例中均降低了组成型STAT活性。此外，在4/5的FLT3内部串联重复（ITD）阳性AML病例和7/13的FLT3野生型（WT）病例中，Akt和丝裂原活化蛋白激酶的磷酸化水平降低。在32D细胞中FLT3-WT、ITD和D835Y的表达表明，Gö6976也是WT和突变型FLT3的有效抑制剂。在AML细胞中，Gö6976使FLT3-ITD病例的存活率降至对照组的55±5%，使FLT3-WT样本的存活率降至69±5%。这些数据可能有助于基于Gö6976的结构鉴定出临床上有用的化合物，可用于治疗MPD和AML。
