产品号 #73472_C
JAK/STAT通路抑制剂；抑制JAK2
总览
TG101348是Janus激酶2（JAK2）的抑制剂，IC₅₀为6 nM。它能抑制活性较低的相关激酶，例如fms相关酪氨酸激酶3（FLT3）、RET和JAK3，IC₅₀值分别为25 nM、17 nM和169 nM（Pardanani et al.）。据推测，TG101348可与其激酶靶标的ATP结合位点结合（Zhou et al.）。
癌症研究
·抑制表达JAK2 V617F或MPL W515L突变的Ba/F3细胞的生长（Pardanani et al.）。
·在JAK2 V617F诱发的造血和骨髓增生性疾病小鼠模型中，降低肿瘤细胞负担并提高生存率（Pardanani et al.; Wernig et al.）。
·在体外和小鼠异种移植模型中，提高对厄洛替尼耐药的非小细胞肺癌细胞对厄洛替尼治疗的敏感性（Zhang et al.）。
·在体外，从染色质中取代BRD4，并抑制多发性骨髓瘤细胞中的c-MYC表达（Ciceri et al.）。
细胞类型
癌细胞及细胞系，白血病/淋巴瘤细胞
种属
人，小鼠，非人灵长类，其它细胞系，大鼠
研究领域
癌症
CAS 编号
936091-26-8
化学式
C₂₇H₃₆N₆O₃S
纯度
≥98%
通路
JAK/STAT
靶点
JAK2
Protocols and Documentation
Find supporting information and directions for use in the Product Information Sheet or explore additional protocols below.
Resources and Publications
Educational Materials (2)
Publications (5)
JAK2 inhibitor TG101348 overcomes erlotinib-resistance in non-small cell lung carcinoma cells with mutated EGF receptor. Oncotarget 2015
Abstract
Non-small cell lung cancer (NSCLC) patients with epidermal growth factor receptor (EGFR) mutations are responsive to EGFR-tyrosine kinase inhibitor (EGFR-TKI). However, NSCLC patients with secondary somatic EGFR mutations are resistant to EGFR-TKI treatment. In this study, we investigated the effect of TG101348 (a JAK2 inhibitor) on the tumor growth of erlotinib-resistant NSCLC cells. Cell proliferation, apoptosis, gene expression and tumor growth were evaluated by diphenyltetrazolium bromide (MTT) assay, flow cytometry, terminal deoxynucleotidyl transferase biotin-dUTP nick end labeling (TUNEL) staining, Western Blot and a xenograft mouse model, respectively. Results showed that erlotinib had a stronger impact on the induction of apoptosis in erlotinib-sensitive PC-9 cells but had a weaker effect on erlotinib-resistant H1975 and H1650 cells than TG101348. TG101348 significantly enhanced the cytotoxicity of erlotinib to erlotinib-resistant NSCLC cells, stimulated erlotinib-induced apoptosis and downregulated the expressions of EGFR, p-EGFR, p-STAT3, Bcl-xL and survivin in erlotinib-resistant NSCLC cells. Moreover, the combined treatment of TG101348 and erlotinib induced apoptosis, inhibited the activation of p-EGFR and p-STAT3, and inhibited tumor growth of erlotinib-resistant NSCLC cells in vivo. Our results indicate that TG101348 is a potential adjuvant for NSCLC patients during erlotinib treatment.
Dual kinase-bromodomain inhibitors for rationally designed polypharmacology. Nature chemical biology 2014
Abstract
Concomitant inhibition of multiple cancer-driving kinases is an established strategy to improve the durability of clinical responses to targeted therapies. The difficulty of discovering kinase inhibitors with an appropriate multitarget profile has, however, necessitated the application of combination therapies, which can pose major clinical development challenges. Epigenetic reader domains of the bromodomain family have recently emerged as new targets for cancer therapy. Here we report that several clinical kinase inhibitors also inhibit bromodomains with therapeutically relevant potencies and are best classified as dual kinase-bromodomain inhibitors. Nanomolar activity on BRD4 by BI-2536 and TG-101348, which are clinical PLK1 and JAK2-FLT3 kinase inhibitors, respectively, is particularly noteworthy as these combinations of activities on independent oncogenic pathways exemplify a new strategy for rational single-agent polypharmacological targeting. Furthermore, structure-activity relationships and co-crystal structures identify design features that enable a general platform for the rational design of dual kinase-bromodomain inhibitors.
Specificity and mechanism-of-action of the JAK2 tyrosine kinase inhibitors ruxolitinib and SAR302503 (TG101348). Leukemia 2014
Abstract
更多信息
| Species | Human, Mouse, Non-Human Primate, Other, Rat |
|---|---|
| Cas Number | 936091-26-8 |
| Chemical Formula | C₂₇H₃₆N₆O₃S |
| Purity | ≥ 98% |
| Target | JAK2 |
| Pathway | JAK/STAT |
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