Altiratinibc-MET/TIE-2/VEGFR inhibitor CAS# 1345847-93-9 |
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Quality Control & MSDS
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Chemical structure
3D structure
| Cas No. | 1345847-93-9 | SDF | Download SDF |
| PubChem ID | 54576299 | Appearance | Powder |
| Formula | C26H21F3N4O4 | M.Wt | 510.46 |
| Type of Compound | N/A | Storage | Desiccate at -20°C |
| Synonyms | DCC-2701 | ||
| Solubility | DMSO : 25 mg/mL (48.98 mM; Need ultrasonic) | ||
| Chemical Name | 1-N'-[4-[2-(cyclopropanecarbonylamino)pyridin-4-yl]oxy-2,5-difluorophenyl]-1-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide | ||
| SMILES | C1CC1C(=O)NC2=NC=CC(=C2)OC3=C(C=C(C(=C3)F)NC(=O)C4(CC4)C(=O)NC5=CC=C(C=C5)F)F | ||
| Standard InChIKey | GNNDEPIMDAZHRQ-UHFFFAOYSA-N | ||
| Standard InChI | InChI=1S/C26H21F3N4O4/c27-15-3-5-16(6-4-15)31-24(35)26(8-9-26)25(36)32-20-12-19(29)21(13-18(20)28)37-17-7-10-30-22(11-17)33-23(34)14-1-2-14/h3-7,10-14H,1-2,8-9H2,(H,31,35)(H,32,36)(H,30,33,34) | ||
| General tips | For obtaining a higher solubility , please warm the tube at 37 ℃ and shake it in the ultrasonic bath for a while.Stock solution can be stored below -20℃ for several months. We recommend that you prepare and use the solution on the same day. However, if the test schedule requires, the stock solutions can be prepared in advance, and the stock solution must be sealed and stored below -20℃. In general, the stock solution can be kept for several months. Before use, we recommend that you leave the vial at room temperature for at least an hour before opening it. |
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| About Packaging | 1. The packaging of the product may be reversed during transportation, cause the high purity compounds to adhere to the neck or cap of the vial.Take the vail out of its packaging and shake gently until the compounds fall to the bottom of the vial. 2. For liquid products, please centrifuge at 500xg to gather the liquid to the bottom of the vial. 3. Try to avoid loss or contamination during the experiment. |
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| Shipping Condition | Packaging according to customer requirements(5mg, 10mg, 20mg and more). Ship via FedEx, DHL, UPS, EMS or other couriers with RT, or blue ice upon request. | ||
| Description | Altiratinib (DCC-2701) is a multi-targeted kinase inhibitor with IC50s of 2.7, 8, 9.2, 9.3, 0.85, 4.6, 0.83 nM for MET, TIE2, VEGFR2, FLT3, Trk1, Trk2, and Trk3 respectively.In Vitro:Altiratinib also inhibits MET isoforms METD1228H, MET D1228N, METY1230C, METY1230D, METY1230H, METM1250T with IC50s of 3.6, 1.3, 1.2, 0.37, 1.5 and 6 nM, respectively. Altiratinib inhibits MET phosphorylation with IC50 values of 0.85 and 2.2 nM, respectively. In the U-87 glioblastoma cell line, MET and HGF are both expressed. Altiratinib blocks autocrine activation of MET phosphorylation in these cells (IC50=6.2 nM). Altiratinib potently inhibits cellular proliferation in MET-amplified EBC-1 and MKN-45 cells, as well as TPM3-TRKA fusion KM-12 cells. Activation of MET is known to increase the motility and invasiveness of cancer cells: Altiratinib inhibits HGF-induced A549 cell migration, with an IC50 of 13 nM. Altiratinib also inhibits FLT3-ITD mutant MV-4-11 cell proliferation with an IC50 of 12 nM[1].In Vivo:A single oral dose of 30 mg/kg Altiratinib leads to >95% inhibition of MET phosphorylation for the entire 24-hour period. A single 10 mg/kg oral dose of Altiratinib exhibits complete inhibition of MET phosphorylation through 12 hours and 73% inhibition at 24 hours postdose. Altiratinib dosed at 10 mg/kg twice a day leads to a significant 90% decrease in BLI signal. Altiratinib exhibits properties amenable to oral administration and exhibits substantial blood–brain barrier penetration, an attribute of significance for eventual treatment of brain cancers and brain metastases[1]. References: | |||||
Altiratinib Dilution Calculator
Altiratinib Molarity Calculator
| 1 mg | 5 mg | 10 mg | 20 mg | 25 mg | |
| 1 mM | 1.959 mL | 9.7951 mL | 19.5902 mL | 39.1803 mL | 48.9754 mL |
| 5 mM | 0.3918 mL | 1.959 mL | 3.918 mL | 7.8361 mL | 9.7951 mL |
| 10 mM | 0.1959 mL | 0.9795 mL | 1.959 mL | 3.918 mL | 4.8975 mL |
| 50 mM | 0.0392 mL | 0.1959 mL | 0.3918 mL | 0.7836 mL | 0.9795 mL |
| 100 mM | 0.0196 mL | 0.098 mL | 0.1959 mL | 0.3918 mL | 0.4898 mL |
| * Note: If you are in the process of experiment, it's necessary to make the dilution ratios of the samples. The dilution data above is only for reference. Normally, it's can get a better solubility within lower of Concentrations. | |||||
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Altiratinib (DCC-2701) is a potent inhibitor of c-MET/TIE-2/VEGFR with IC50 values of 2.7, 8.0 and 9.2 nM, respectively [1].
Hepatocyte growth factor receptor (c-MET) is a tyrosine kinase receptor for hepatocyte growth factor and is essential for wound healing and embryonic development. TEK tyrosine kinase (TIE-2) is a receptor for angiopoietin-1 (ANG-1) and is important for endothelial cell-smooth muscle cell communication. VEGFR is a tyrosine kinase receptor for vascular endothelial growth factor that involved in both vasculogenesis and angiogenesis.
Altiratinib (DCC-2701) is a potent c-MET/TIE-2/VEGFR inhibitor. Altiratinib potently inhibited MET kinase and activating oncogenic MET mutations and also inhibited TRKA, TRKB and TRKC kinases with IC50 values of 0.85, 4.6, and 0.83 nM, respectively. In EBC-1 NSCLC and MKN-45 gastric cancer cell lines overexpressing MET, altiratinib inhibited MET phosphorylation with IC50 values of 0.85 and 2.2 nM, respectively. In VEGF-stimulated HUVECs, altiratinib inhibited VEGFR2 phosphorylation with IC50 value of 4.7 nM. In HUVECs and EA.hy926 cells, altiratinib inhibited TIE2 phosphorylation stimulated by ANG-1 with IC50 values of 1.0 and 2.6 nM, respectively [1].
In the MET-amplified MKN-45 xenograft model, altiratinib (30 mg/kg) inhibited MET phosphorylation by >95% for the 24-hour period [1]. In nude mouse xenografted SKOV3 cells, DCC-2701 (10 or 20 mg/kg for 28 days) significantly reduced tumor burden by 53% and 52%, respectively [2].
References:
[1]. Smith BD, Kaufman MD, Leary CB, et al. Altiratinib Inhibits Tumor Growth, Invasion, Angiogenesis, and Microenvironment-Mediated Drug Resistance via Balanced Inhibition of MET, TIE2, and VEGFR2. Mol Cancer Ther, 2015.
[2]. Kwon Y, Smith BD, Zhou Y, et al. Effective inhibition of c-MET-mediated signaling, growth and migration of ovarian cancer cells is influenced by the ovarian tissue microenvironment. Oncogene, 2015, 34(2): 144-153.
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Altiratinib Inhibits Tumor Growth, Invasion, Angiogenesis, and Microenvironment-Mediated Drug Resistance via Balanced Inhibition of MET, TIE2, and VEGFR2.[Pubmed:26285778]
Mol Cancer Ther. 2015 Sep;14(9):2023-34.
Altiratinib (DCC-2701) was designed based on the rationale of engineering a single therapeutic agent able to address multiple hallmarks of cancer (1). Specifically, Altiratinib inhibits not only mechanisms of tumor initiation and progression, but also drug resistance mechanisms in the tumor and microenvironment through balanced inhibition of MET, TIE2 (TEK), and VEGFR2 (KDR) kinases. This profile was achieved by optimizing binding into the switch control pocket of all three kinases, inducing type II inactive conformations. Altiratinib durably inhibits MET, both wild-type and mutated forms, in vitro and in vivo. Through its balanced inhibitory potency versus MET, TIE2, and VEGFR2, Altiratinib provides an agent that inhibits three major evasive (re)vascularization and resistance pathways (HGF, ANG, and VEGF) and blocks tumor invasion and metastasis. Altiratinib exhibits properties amenable to oral administration and exhibits substantial blood-brain barrier penetration, an attribute of significance for eventual treatment of brain cancers and brain metastases.
Novel MET/TIE2/VEGFR2 inhibitor altiratinib inhibits tumor growth and invasiveness in bevacizumab-resistant glioblastoma mouse models.[Pubmed:26965451]
Neuro Oncol. 2016 Sep;18(9):1230-41.
BACKGROUND: Glioblastoma highly expresses the proto-oncogene MET in the setting of resistance to bevacizumab. MET engagement by hepatocyte growth factor (HGF) results in receptor dimerization and autophosphorylation mediating tumor growth, invasion, and metastasis. Evasive revascularization and the recruitment of TIE2-expressing macrophages (TEMs) are also triggered by anti-VEGF therapy. METHODS: We investigated the activity of Altiratinib (a novel balanced inhibitor of MET/TIE2/VEGFR2) against human glioblastoma stem cell lines in vitro and in vivo using xenograft mouse models. The biological activity of Altiratinib was assessed in vitro by testing the expression of HGF-stimulated MET phosphorylation as well as cell viability after Altiratinib treatment. Tumor volume, stem cell and mesenchymal marker levels, microvessel density, and TIE2-expressing monocyte infiltration were evaluated in vivo following treatment with a control, bevacizumab alone, bevacizumab combined with Altiratinib, or Altiratinib alone. RESULTS: In vitro, HGF-stimulated MET phosphorylation was completely suppressed by Altiratinib in GSC17 and GSC267, and Altiratinib markedly inhibited cell viability in several glioblastoma stem cell lines. More importantly, in multiple xenograft mouse models, Altiratinib combined with bevacizumab dramatically reduced tumor volume, invasiveness, mesenchymal marker expression, microvessel density, and TIE2-expressing monocyte infiltration compared with bevacizumab alone. Furthermore, in the GSC17 xenograft model, Altiratinib combined with bevacizumab significantly prolonged survival compared with bevacizumab alone. CONCLUSIONS: Together, these data suggest that Altiratinib may suppress tumor growth, invasiveness, angiogenesis, and myeloid cell infiltration in glioblastoma. Thus, Altiratinib administered alone or in combination with bevacizumab may overcome resistance to bevacizumab and prolong survival in patients with glioblastoma.
