产品号 #72932_C
Tyrosine kinase inhibitor; Inhibits EGFR, HER2, JAK2, JAK3 and STAT5a/b
概述
AG-490 is a member of the tyrphostin family of small molecule inhibitors of tyrosine kinases including EGFR (Gazit et al.), HER2 (Gazit et al.), JAK2 (Burger et al.), JAK3 (Brown et al.), and STAT5a/b (Wang et al.) with IC₅₀ values of 0.1, 13.5, 11 and 12 μM, respectively. AG-490 does not inhibit LCK, LYN, BTK, SYK, or SRC tyrosine kinases (Meydan et al.).
DIFFERENTIATION
· Induces differentiation of mouse (OG2) embryonic stem cells, with LIF and BMP4 (Chen et al.).
CANCER RESEARCH
· Blocks growth of acute lymphoblastic leukemia pre-B cells by inducing programmed cell death, via inhibition of JAK2 (Meydan et al.).
· Inhibits proliferation of cervical carcinoma cell lines (Soto-Cruz et al.).
· Inhibits STAT3 phosphorylation and induced translocation of beta-catenin to the cytoplasm in the colorectal cell line SW480 (Kawada et al.).
· Induces S phase arrest of GL15 glioblastoma cells via JAK2 inhibition (Sciaccaluga et al.).
· Inhibits EGF-dependant proliferation of NIH3T3 cell lines (Gazit et al.).
· Blocks IL-2 induced thymidine incorporation in T-cell lines (Wang et al.).
Cell Type
Cancer Cells and Cell Lines, Leukemia/Lymphoma Cells, Pluripotent Stem Cells, T Cells
Species
Human, Mouse, Non-Human Primate, Other, Rat
Application
Differentiation
Area of Interest
Cancer, Stem Cell Biology
CAS Number
133550-30-8
Chemical Formula
C₁₇H₁₄N₂O₃
Purity
≥ 98%
Pathway
JAK/STAT, Tyrosine Kinase
Target
EGFR, HER2, JAK2, JAK3, STAT5
Protocols and Documentation
Find supporting information and directions for use in the Product Information Sheet or explore additional protocols below.
Applications
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Resources and Publications
Educational Materials (2)
Publications (9)
Janus kinase inhibitor INCB20 has antiproliferative and apoptotic effects on human myeloma cells in vitro and in vivo Molecular Cancer Therapeutics 2009
Abstract
Protein tyrosine kinases of the Janus kinase (JAK) family are associated with many cytokine receptors, which, on ligand binding, regulate important cellular functions such as proliferation, survival, and differentiation. In multiple myeloma, JAKs may be persistently activated due to a constant stimulation by interleukin (IL)-6, which is produced in the bone marrow environment. INCB20 is a synthetic molecule that potently inhibits all members of the JAK family with a 100- to 1,000-fold selectivity for JAKs over textgreater70 other kinases. Treatment of multiple myeloma cell lines and patient tumor cells with INCB20 resulted in a significant and dose-dependent inhibition of spontaneous as well as IL-6-induced cell growth. Importantly, multiple myeloma cell growth was inhibited in the presence of bone marrow stromal cells. The IL-6 dependent cell line INA-6 was particularly sensitive to the drug (IC50textless1 micromol/L). Growth suppression of INA-6 correlated with an increase in the percentage of apoptotic cells and inhibition of signal transducer and activator of transcription 3 phosphorylation. INCB20 also abrogated the protective effect of IL-6 against dexamethasone by blocking phosphorylation of SHP-2 and AKT. In contrast, AKT phosphorylation induced by insulin-like growth factor-I remained unchanged, showing selectivity of the compound. In a s.c. severe combined immunodeficient mouse model with INA-6, INCB20 significantly delayed INA-6 tumor growth. Our studies show that disruption of JAKs and downstream signaling pathways may both inhibit multiple myeloma cell growth and survival and overcome cytokine-mediated drug resistance, thereby providing the preclinical rationale for the use of JAK inhibitors as a novel therapeutic approach in multiple myeloma.
The Tyrphostin B42 Inhibits Cell Proliferation and HER-2 Autophosphorylation in Cervical Carcinoma Cell Lines Cancer Investigation 2008
Abstract
The HER family receptors have an important role controlling cell growth and differentiation. Although the activity of the HER-2 receptor is strictly controlled in normal cells, its overexpression plays a pivotal role in transformation and tumorigenesis. Constitutive phosphorylation of HER-2 protein has been implicated in conferring uncontrolled growth to mammary cancer cells, and to a lesser extent, with adenocarcinoma of uterus, cervix, fallopian tube, and endometrium. This study addresses the role of HER-2 in cervical carcinoma. Firstly, we demonstrate the presence of HER-2 protein expression by flow cytometry in two new cervical carcinoma cell lines CALO and INBL. Secondly, we use the specific tyrosine kinase inhibitors, Tyrphostins to examine HER-2 regulation by the crystal violet assay. Thirdly, we use western blot analysis to assess the state of HER-2 phosphorylation. The most efficient agent, Tyrphostin B42, known as an inhibitor of epithelial growth factor receptor, arrested cervical carcinoma cell lines growth in vitro at micromolar concentrations within 72 h of application. Tyrphostin B42 inhibited the HER2 signal-regulated kinase pathway, as observed by the reduction in the phosphorylated forms of HER2. The loss of phosphorylated forms of HER2 at early time points after Tyrphostin B42 application was associated with suppression of cell growth. Thus, the inhibition of the proliferation of our cervical carcinoma cell lines by Tyrphostin B42 is associated with inhibition of HER2 protein kinase signal.
Constitutive phosphorylation of Janus kinase 2 in the GL15 glioblastoma derived human cell line. Oncology reports 2007
Abstract
The notion that gliomas could originate from mutated glial precursor cells highlights the possibility of modulating the proliferative and migratory behaviour of glioma cells by acting on the molecular mechanisms operative during the development of the Central Nervous System (CNS), but absent in the normal adult brain. We show that the GL15 glioblastoma derived human cell line displays a high expression of nestin which, combined with the previously demonstrated high expression of vimentin, constitutes a characteristic of astrocyte restricted precursors. We also show that, in analogy with some leukaemia cells, GL15 cells display the constitutively phosphorylated form of Janus kinase 2 (JAK2), a tyrosine kinase expressed during CNS development but undetectable in the normal adult brain. The constitutive activation of JAK2 does not result from chromosomal aberrations involving the JAK2 gene, but most probably from abnormally activated transduction systems operative in glioblastoma cells. We then investigated the effects of tyrphostin AG490, an inhibitor of JAK2 autophosphorylation, on GL15 cell growth. In the absence of exogenous growth factors and cytokines, 10 microM tyrphostin AG490 induces an S phase arrest, combined with a partial impairment of the G2 phase of the cell cycle. The abnormally activated JAK2 could then potentially represent a target for a selective pharmacological approach in glioblastoma cells in which a combination of glial precursor characteristics and genetic alterations occurs.
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