| Size | Price | Stock | Qty |
|---|---|---|---|
| 1mg |
|
||
| 5mg | |||
| Other Sizes |
| Targets |
PDGFR2
RET kinase (wild-type and mutant forms). Zeteletinib is a potent RET inhibitor with nanomolar potency against wild-type RET and clinically relevant mutations, exhibiting >300-fold selectivity over VEGFR2. |
|---|---|
| ln Vitro |
193 nM Zeteletinib (BOS-172738; DS-5010) inhibited RET and platelet-derived growth factor receptor (PDGFR) alpha/beta by more than 80% in biochemical assays of 106 kinases. Even in the presence of high ATP concentrations, Zeteletinib's IC50 values against RET and RET -GKm (V804L) were single digit nano-molar; in addition, it was more than 1000 nM against KDR[1].
Zeteletinib demonstrates potent inhibition of RET kinase activity, with a Ki value of less than 1 nM. It maintains strong activity against various RET resistance mutations, including the solvent front G810R mutation. In cell-based assays, it effectively inhibits the proliferation of RET-driven cancer cell lines. |
| ln Vivo |
Zeteletinib (BOS-172738; DS-5010) dosed at 10 mg/kg twice daily (bid) causes tumor shrinkage in a Ba/F3-RET subcutaneous tumor model[1]. Tumor regression was observed in an LC2/ad NSCLC xenograft model with the RET-CCDC6 fusion gene when zeteletinib was dosed at 1 mg/kg three times a day (tid)[1].
In animal models, oral administration of zeteletinib results in significant regression of RET-driven tumor xenografts. It has shown superior brain penetration, making it effective against intracranial tumor models. Phase 1 clinical trials demonstrated durable responses in patients with RET-altered tumors. |
| Enzyme Assay |
Cell-free RET kinase assays are performed using recombinant RET enzyme (wild-type or mutant) and a peptide substrate in the presence of ATP. The compound is incubated with the enzyme for 30-60 minutes, and kinase activity is measured by a luminescence-based ADP detection system. IC50 values are calculated from dose-response curves.
|
| Cell Assay |
RET-dependent cancer cell lines (e.g., LC-2/ad) are seeded in 96-well plates and treated with increasing concentrations of zeteletinib for 72 hours. Cell viability is assessed using the CellTiter-Glo luminescent cell viability assay. The IC50 is calculated by nonlinear regression analysis of the dose-response curves using software like GraphPad Prism.
|
| Animal Protocol |
Female BALB/c nude mice are subcutaneously inoculated with RET-driven tumor cells. When tumors reach an appropriate volume, zeteletinib is administered orally once daily. Tumor volumes are measured with calipers twice weekly. At the end of the study, tumors are excised for pharmacokinetic and pharmacodynamic analyses, such as measuring RET phosphorylation levels.
|
| ADME/Pharmacokinetics |
Zeteletinib is orally bioavailable and brain-penetrant. Following oral administration, it achieves high systemic exposure with a moderate half-life, allowing for once-daily dosing. The compound is metabolized in the liver, primarily by CYP3A4, and its clearance is moderate. It has a favorable volume of distribution, indicating good tissue penetration.
|
| Toxicity/Toxicokinetics |
In preclinical safety studies, zeteletinib was generally well-tolerated at therapeutic doses, with no significant off-target toxicities reported. The most common adverse events in clinical trials were fatigue, nausea, and elevated liver enzymes, which were manageable and reversible. Comprehensive toxicology assessments are ongoing.
|
| References |
|
| Additional Infomation |
Zeteletinib is a highly bioavailable, selective inhibitor of proto-oncogene receptor tyrosine kinase (RET) in its wild-type, fusion, and mutant forms (including gating mutations), exhibiting potential antitumor activity. After oral administration, zeteletinib selectively binds to and inhibits RET activity. This leads to the suppression of the growth of tumor cells with enhanced RET activity. RET overexpression, activating mutations, and fusions result in the upregulation and/or overactivation of RET tyrosine kinase activity in various cancer cell types; dysregulation of RET activity plays a crucial role in the development and progression of these cancers.
Other information: Zeteletinib (DS-5010) is a next-generation selective RET inhibitor developed to overcome acquired resistance to first-generation inhibitors. It has received Fast Track designation from the FDA for the treatment of patients with RET fusion-positive NSCLC. Preclinically, it has shown a favorable safety profile and robust brain penetration, making it a candidate for treating brain metastases. |
| Molecular Formula |
C25H23F3N4O4
|
|---|---|
| Molecular Weight |
500.469736337662
|
| Exact Mass |
500.167
|
| CAS # |
2216753-97-6
|
| Related CAS # |
Zeteletinib hemiadipate;2375837-06-0
|
| PubChem CID |
134391533
|
| Appearance |
White to light yellow solid powder
|
| LogP |
4.6
|
| Hydrogen Bond Donor Count |
1
|
| Hydrogen Bond Acceptor Count |
10
|
| Rotatable Bond Count |
7
|
| Heavy Atom Count |
36
|
| Complexity |
755
|
| Defined Atom Stereocenter Count |
0
|
| SMILES |
FC(C(C)(C)C1C=C(NC(CC2=CN=C(C=C2)C2=CN=C3C=C(C(=CC3=C2)OC)OC)=O)ON=1)(F)F
|
| InChi Key |
KOLQINCWMXQEOF-UHFFFAOYSA-N
|
| InChi Code |
InChI=1S/C25H23F3N4O4/c1-24(2,25(26,27)28)21-11-23(36-32-21)31-22(33)7-14-5-6-17(29-12-14)16-8-15-9-19(34-3)20(35-4)10-18(15)30-13-16/h5-6,8-13H,7H2,1-4H3,(H,31,33)
|
| Chemical Name |
2-[6-(6,7-dimethoxyquinolin-3-yl)pyridin-3-yl]-N-[3-(1,1,1-trifluoro-2-methylpropan-2-yl)-1,2-oxazol-5-yl]acetamide
|
| 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) |
DMSO: 100 mg/mL (199.81 mM)
|
|---|---|
| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.5 mg/mL (5.00 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 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. Solubility in Formulation 2: ≥ 2.5 mg/mL (5.00 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in 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 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly. Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution. View More
Solubility in Formulation 3: ≥ 2.5 mg/mL (5.00 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution. |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 1.9981 mL | 9.9906 mL | 19.9812 mL | |
| 5 mM | 0.3996 mL | 1.9981 mL | 3.9962 mL | |
| 10 mM | 0.1998 mL | 0.9991 mL | 1.9981 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.
Link: https://clinicaltrials.gov/ct2/show/NCT03780517
Conditions:Advanced Nonhaematologic MalignanciesProducts are for research use only; We do not sell to patients
Copyright 2020 InvivoChem LLC | All Rights Reserved
