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1.  MS-1020 is a novel small molecule that selectively inhibits JAK3 activity 
British journal of haematology  2009;148(1):132-143.
To identify JAK/STAT signaling inhibitors, we performed a cell-based high throughput screening using a plant extract library and identified Nb-(α-hydroxynaphthoyl)serotonin called MS-1020 as a novel JAK3 inhibitor. MS-1020 potently inhibited persistently-active STAT3 in a cell type-specific manner. Upon further examination, we found that MS-1020 selectively blocks constitutively-active JAK3. MS-1020 consistently suppressed IL-2-induced JAK3/STAT5 signaling but not prolactin-induced JAK2/STAT5 signaling. Furthermore, MS-1020 affected cell viability only in cancer cells harboring persistently-active JAK3/STATs, and in vitro kinase assays showed MS-1020 binds directly with JAK3, blocking its catalytic activity. Therefore, our study suggested that this reagent selectively inhibits JAK3 and subsequently leads to a block in STAT signaling. Finally, we showed MS-1020 decreases cell survival by inducing apoptosis via down-regulating anti-apoptotic gene expression. Our study suggests that MS-1020 may have therapeutic potential in the treatment of cancers harboring aberrant JAK3 signaling.
PMCID: PMC3034357  PMID: 19793252
JAK/STAT; cancer; small molecule inhibitor; plant extracts; cell-based high throughput screening; Drosophila
2.  Development of a high-throughput cell-based reporter assay for screening JAK3 inhibitors 
Journal of biomolecular screening  2011;16(4):443-449.
JAK3 has become an ideal target for the therapeutic treatment of immune-related diseases, as well as for the prevention of organ allograft rejection. A number of JAK3 inhibitors have been identified by in vitro biochemical enzymatic assays, but the majority display significant off-target effects on JAK2. Therefore, there is an urgent need to develop new experimental approaches to identify compounds that specifically inhibit JAK3. Here, we showed that in 32D/IL-2Rβ cells, STAT5 becomes phosphorylated by IL-3/JAK2- or IL-2/JAK3-dependent pathway. Importantly, the selective JAK3 inhibitor CP-690,550 blocked the phosphorylation as well as the nuclear translocation of STAT5 following treatment of cells with IL-2, but not with IL-3. In an attempt to use the cells for large-scale chemical screens to identify JAK3 inhibitors, we established a cell line 32D/IL-2Rβ/6×STAT5 stably expressing a well-characterized STAT5 reporter gene. Treatment of this cell line with IL-2 or IL-3 dramatically increased the reporter activity in a high-throughput format. As expected, JAK3 inhibitors, CP-690,550 and JAK3 inhibitor VI, selectively inhibited the activity of the 6×STAT5 reporter following treatment with IL-2. By contrast, the pan-JAK inhibitor Curcumin non-selectively inhibited the activity of this reporter following treatment with either IL-2 or IL-3. Thus, this study indicates that our STAT5 reporter cell line can be used as an efficacious cellular model for chemical screens to identify low-molecular-weight inhibitors specific for JAK3.
PMCID: PMC3237679  PMID: 21393628
Assay development; Cytokine; JAK3 inhibitors; STAT5 reporter; high-throughput chemical screening
3.  Benzoxathiol derivative BOT-4-one suppresses L540 lymphoma cell survival and proliferation via inhibition of JAK3/STAT3 signaling 
Experimental & Molecular Medicine  2011;43(5):313-321.
Persistently activated JAK/STAT3 signaling pathway plays a pivotal role in various human cancers including major carcinomas and hematologic tumors, and is implicated in cancer cell survival and proliferation. Therefore, inhibition of JAK/STAT3 signaling may be a clinical application in cancer therapy. Here, we report that 2-cyclohexylimino-6-methyl-6,7-dihydro-5H-benzo [1,3]oxathiol-4-one (BOT-4-one), a small molecule inhibitor of JAK/STAT3 signaling, induces apoptosis through inhibition of STAT3 activation. BOT-4-one suppressed cytokine (upd)-induced tyrosine phosphorylation and transcriptional activity of STAT92E, the sole Drosophila STAT homolog. Consequently, BOT-4-one significantly inhibited STAT3 tyrosine phosphorylation and expression of STAT3 downstream target gene SOCS3 in various human cancer cell lines, and its effect was more potent in JAK3-activated Hodgkin's lymphoma cell line than in JAK2-activated breast cancer and prostate cancer cell lines. In addition, BOT-4-one-treated Hodgkin's lymphoma cells showed decreased cell survival and proliferation by inducing apoptosis through down-regulation of STAT3 downstream target anti-apoptotic gene expression. These results suggest that BOT-4-one is a novel small molecule inhibitor of JAK3/STAT3 signaling and may have therapeutic potential in the treatment of human cancers harboring aberrant JAK3/STAT3 signaling, specifically Hodgkin's lymphoma.
PMCID: PMC3104254  PMID: 21499010
BOT-4-one; cancer; JAK; small molecule inhibitor, apoptosis; STAT3
4.  NSC114792, a novel small molecule identified through structure-based computational database screening, selectively inhibits JAK3 
Molecular Cancer  2010;9:36.
Human or animals lacking either JAK3 or the common gamma chain (γc) expression display severe combined immunodeficiency disease, indicating the crucial role of JAK3 in T-cell development and the homeostasis of the immune system. JAK3 has also been suggested to contribute to the pathogenesis of tumorigenesis. Recent studies identified activating JAK3 mutations in patients with various hematopoietic malignancies, including acute megakaryoblastic leukemia. Importantly, functional analyses of some of those JAK3 mutations have been shown to cause lethal hematopoietic malignancies in animal models. These observations make JAK3 an ideal therapeutic target for the treatment of various human diseases. To identify novel small molecule inhibitors of JAK3, we performed structure-based virtual screen using the 3D structure of JAK3 kinase domain and the NCI diversity set of compounds.
We identified NSC114792 as a lead compound. This compound directly blocked the catalytic activity of JAK3 but not that of other JAK family members in vitro. In addition, treatment of 32D/IL-2Rβ cells with the compound led to a block in IL-2-dependent activation of JAK3/STAT5 but not IL-3-dependent activation of JAK2/STAT5. Consistent with the specificity of NSC114792 for JAK3, it selectively inhibited persistently-activated JAK3, but failed to affect the activity of other JAK family members and other oncogenic kinases in various cancer cell lines. Finally, we showed that NSC114792 decreases cell viability by inducing apoptosis through down-regulating anti-apoptotic gene expression only in cancer cells harboring persistently-active JAK3.
NSC114792 is a lead compound that selectively inhibits JAK3 activity. Therefore, our study suggests that this small molecule inhibitor of JAK3 can be used as a starting point to develop a new class of drugs targeting JAK3 activity, and may have therapeutic potential in various diseases that are caused by aberrant JAK3 activity.
PMCID: PMC2830973  PMID: 20149240

Results 1-4 (4)