| Size | Price | Stock | Qty |
|---|---|---|---|
| 5mg |
|
||
| 10mg |
|
||
| 25mg |
|
||
| 50mg |
|
||
| 100mg |
|
||
| 250mg |
|
||
| 500mg |
|
||
| Other Sizes |
|
Purity: ≥98%
Altiratinib (also known as DCC-2701 and DP-5164) is an orally active, highly potent and selective multi-kinase inhibitor with IC50 values of 2.7, 8, 9.2, 9.3, 0.85, 4.6, 0.83 nM for MET, TIE2, VEGFR2, FLT3, Trk1, Trk2, and Trk3. The rationale behind its design was to create a single therapeutic agent that could address several of the characteristics of cancer. In particular, through balanced inhibition of MET, TIE2 (TEK), and VEGFR2 (KDR) kinases, altiratinib inhibits not only mechanisms of tumor initiation and progression but also drug resistance mechanisms in the tumor and microenvironment. In TPM3-TRKA fusion KM-12 cells, MET-amplified EBC-1 and MKN-45 cells, as well as both, atrialatinib significantly suppresses cellular proliferation. Altiratinib has characteristics that make it suitable for oral administration. It also has significant blood-brain barrier penetration, which is important for the potential treatment of brain metastases and cancers.
| Targets |
VEGFR2 (IC50 = 9.2 nM); Trk1 (IC50 = 0.85 nM); Trk2 (IC50 = 4.6 nM); Trk3 (IC50 = 0.93 nM); MET (IC50 = 2.7 nM); TIE2 (IC50 = 8 nM); FLT3 (IC50 = 9.3 nM)
|
|
|---|---|---|
| ln Vitro |
|
|
| ln Vivo |
|
|
| Enzyme Assay |
The pyruvate kinase/lactate dehydrogenase (PK/LDH) system was used to measure the amount of kinase activity. In Supplementary Table S2, kinases are described. Test compound and assay mixtures were combined. The reaction could be started right away or after preincubation by adding ATP. 30°C was used to measure the absorbance at 340 nm. Using Prism software (GraphPad), reaction rates were compared to controls, and IC50 values were computed. Off-rate kinetics from MET were determined in accordance with earlier publications. Competitive or noncompetitive inhibition against ATP was assessed using the PK/LDH assay in a Michaelis-Menten analysis. With IC50s of 3.6, 1.3, 1.2, 0.37, 1.5, and 6 nM, respectively, altriatinib also inhibits the MET isoforms METD1228H, MET D1228N, METY1230C, METY1230D, METY1230H, and METM1250T. With IC50 values of 0.85 and 2.2 nM, respectively, altriatinib inhibits MET phosphorylation. Both HGF and MET are expressed in the U-87 glioblastoma cell line. In these cells, altiratinib inhibits autocrine activation of MET phosphorylation (IC50=6.2 nM). In MET-amplified EBC-1 and MKN-45 cells as well as TPM3-TRKA fusion KM-12 cells, atrialatinib potently inhibits cellular proliferation. It is well known that MET activation increases cancer cell motility and invasiveness: With an IC50 of 13 nM, alteratidinib prevents A549 cell migration that is triggered by HGF. Altiratinib also has an IC50 of 12 nM for inhibiting the proliferation of FLT3-ITD mutant MV-4-11 cells.
|
|
| Cell Assay |
Assay plates are filled with aflatinib. Cells are added to 384-well plates (A375 and HCT-116: 625 cells/well; BT-474, KM-12, PC-3, and U-87-MG: 1,250 cells/well) or 96-well plates (EBC-1, M-NFS-60, and SK-MEL-28: 2,500 cells/well; MKN-45: 5,000 cells/well; MV-4-11: 10,000 cells/well). Incubation lasts for 72 hours on plates. Resazurin is used in plate readers with excitation at 540 nm and emission at 600 nm to quantify viable cells[1].
|
|
| Animal Protocol |
Mice: The subcutaneous inoculation of female naked mice occurs. Mice are randomly assigned to groups and dosed once orally with 0.4% HMPC (n = 3); 30 mg/kg (n = 21); or 10 mg/kg (n = 21) of altiratinib on days 9 to 10, when tumor volumes have averaged 326 mg. Tumor samples and whole blood are taken at predetermined intervals. Analysis of pharmacokinetics is done. Western blot assay procedures are used to process tumor samples[1].
|
|
| References |
| Molecular Formula |
C26H21F3N4O4
|
|
|---|---|---|
| Molecular Weight |
510.46
|
|
| Exact Mass |
510.15
|
|
| Elemental Analysis |
C, 61.18; H, 4.15; F, 11.17; N, 10.98; O, 12.54
|
|
| CAS # |
1345847-93-9
|
|
| Related CAS # |
|
|
| Appearance |
Solid powder
|
|
| 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
|
|
| InChi Key |
GNNDEPIMDAZHRQ-UHFFFAOYSA-N
|
|
| InChi Code |
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)
|
|
| Chemical Name |
1-N'-[4-[2-(cyclopropanecarbonylamino)pyridin-4-yl]oxy-2,5-difluorophenyl]-1-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide
|
|
| Synonyms |
|
|
| HS Tariff Code |
2934.99.9001
|
|
| Storage |
Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month |
|
| Shipping Condition |
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
|
| Solubility (In Vitro) |
|
|||
|---|---|---|---|---|
| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.5 mg/mL (4.90 mM) (saturation unknown) in 10% DMSO + 40% PEG300 +5% Tween-80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 + to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL. Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution. (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 1.9590 mL | 9.7951 mL | 19.5902 mL | |
| 5 mM | 0.3918 mL | 1.9590 mL | 3.9180 mL | |
| 10 mM | 0.1959 mL | 0.9795 mL | 1.9590 mL |
*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.
Calculation results
Working concentration： mg/mL；
Method for preparing DMSO stock solution： mg drug pre-dissolved in μL DMSO (stock solution concentration mg/mL). Please contact us first if the concentration exceeds the DMSO solubility of the batch of drug.
Method for preparing in vivo formulation:：Take μL DMSO stock solution, next add μL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O，mix and clarify.
(1) Please be sure that the solution is clear before the addition of next solvent. Dissolution methods like vortex, ultrasound or warming and heat may be used to aid dissolving.
(2) Be sure to add the solvent(s) in order.
A, primary tumor growth in the PyMT breast cancer model treated with vehicle, paclitaxel (10 mg/kg i.v. every 5 days), altiratinib 15 mg/kg twice daily, or combination. B, quantitation of TIE2 cellular content within the primary tumor. C, quantitation of lung metastases. D, primary tumor growth in the A375 melanoma xenograft model. E, quantification of tumor vascularization determined with anti-CD31 antibody.Mol Cancer Ther.2015 Sep;14(9):2023-34. |
|---|
A and B, inhibition of phosphorylated TIE2 (pTIE2) or phosphorylated TRKA (pTRKA) in CHO cells, depicting percentage inhibition of pTIE2 or pTRKA at various time points after washout of altiratinib. C, altiratinib inhibition of cellular proliferation and survival pathways in the B-RAF V600E SK-MEL-5 melanoma cell line stimulated with HGF and restoration of sensitivity to dabrafenib. D, altiratinib inhibition of MET phosphorylation after a single oral dose of 10 mg/kg in the MKN-45 xenograft pharmacodynamic model. E and F, efficacy in the MKN-45 gastric cancer xenograft model.Mol Cancer Ther.2015 Sep;14(9):2023-34. |
A, evaluation of tumor volume after 2 weeks of treatment in the orthotopic U-87-MG glioma model. Tumor volume was quantitated by mean luciferase signal. B, FLOW quantitation of circulating TIE2+(open bars) and TIE2+/MET+(black bars) monocytes after 5 weeks of treatment. C, Kaplan–Meier survival plot in the orthotopic U-87-MG glioma model.Mol Cancer Ther.2015 Sep;14(9):2023-34. |
A, chemical structure of altiratinib. B, docked structure of altiratinib into MET kinase. C, view of the docked structure highlighting deep penetration of altiratinibs para-fluorophenyl ring into the switch pocket (yellow residues).Mol Cancer Ther.2015 Sep;14(9):2023-34. |
|---|
Products are for research use only; We do not sell to patients
Copyright 2020 InvivoChem LLC | All Rights Reserved
COA
