Pediatrics-Hematology/Oncology, New York Medical College, Valhalla, NY, USA.
Br J Haematol. 2010 Jan;148(1):132-43. doi: 10.1111/j.1365-2141.2009.07925.x. Epub 2009 Sep 29.
In order to identify Janus kinase/signal transducer and activator of transcription (JAK/STAT) signalling inhibitors, a cell-based high throughput screening was performed using a plant extract library that identified Nb-(alpha-hydroxynaphthoyl)serotonin called MS-1020 as a novel JAK3 inhibitor. MS-1020 potently inhibited persistently-active STAT3 in a cell type-specific manner. Further examination showed that MS-1020 selectively blocked constitutively-active JAK3 and consistently suppressed interleukin-2-induced JAK3/STAT5 signalling but not prolactin-induced JAK2/STAT5 signalling. Furthermore, MS-1020 affected cell viability only in cancer cells harbouring persistently-active JAK3/STATs, and in vitro kinase assays showed MS-1020 binds directly with JAK3, blocking its catalytic activity. Therefore, the present study suggested that this reagent selectively inhibits JAK3 and subsequently leads to a block in STAT signalling. Finally, MS-1020 decreased cell survival by inducing apoptosis via down-regulation of anti-apoptotic gene expression. These results suggest that MS-1020 may have therapeutic potential in the treatment of cancers harbouring aberrant JAK3 signalling.
为了鉴定 Janus 激酶/信号转导子和转录激活子（JAK/STAT）信号抑制剂，采用植物提取物文库进行了基于细胞的高通量筛选，鉴定出 Nb-（α-羟基萘酰基）血清素，称为 MS-1020，是一种新型 JAK3 抑制剂。MS-1020 以细胞类型特异性的方式强烈抑制持续激活的 STAT3。进一步的研究表明，MS-1020 选择性地阻断组成性激活的 JAK3，并一致抑制白细胞介素-2 诱导的 JAK3/STAT5 信号，但不抑制催乳素诱导的 JAK2/STAT5 信号。此外，MS-1020 仅在携带持续激活的 JAK3/STAT 的癌细胞中影响细胞活力，体外激酶测定表明 MS-1020 直接与 JAK3 结合，阻断其催化活性。因此，本研究表明该试剂选择性地抑制 JAK3，随后导致 STAT 信号阻断。最后，MS-1020 通过下调抗凋亡基因的表达诱导细胞凋亡，从而降低细胞存活率。这些结果表明，MS-1020 可能在治疗具有异常 JAK3 信号的癌症方面具有治疗潜力。
