Agerafenib (RXDX-105)
For research use only.
Catalog No.S8015 Synonyms: CEP-32496
6 publications
CAS No. 1188910-76-0
Agerafenib (RXDX-105, CEP-32496) is a highly potent inhibitor of BRAF(V600E/WT) and c-Raf with Kd of 14 nM/36 nM and 39 nM, also potent to Abl-1, c-Kit, Ret (c-Ret), PDGFRβ and VEGFR2, respectively; insignificant affinity for MEK-1, MEK-2, ERK-1 and ERK-2. Phase 1/2.
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Biological Activity
| Description | Agerafenib (RXDX-105, CEP-32496) is a highly potent inhibitor of BRAF(V600E/WT) and c-Raf with Kd of 14 nM/36 nM and 39 nM, also potent to Abl-1, c-Kit, Ret (c-Ret), PDGFRβ and VEGFR2, respectively; insignificant affinity for MEK-1, MEK-2, ERK-1 and ERK-2. Phase 1/2. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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| Features | High binding affinity for both BRAF (V600E) mutation and related c-Raf, but no significant affinity for other kinases of MAPK pathway. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Targets |
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| In vitro |
CEP-32496 inhibits A375 cell (BRAFV600E) proliferation with EC50 of 78 nM. CEP-32496 exhibits more sensitive cytotoxicity for tumor cell lines (A375, SK-MEL-28, Colo-205, Colo-679, and HT-144) expressing mutant BRAF than those expressing wild-type BRAF (HCT116, Hs578T, LNCaP, DU145, and PC-3). [1] CEP-32496 inhibits mitogen-activated protein (MAP)/extracellular signal-regulated (ER) kinase (MEK) phosphorylation (pMEK) in human melanoma (A375) and colorectal cancer (Colo-205) cell lines with IC50 of 78 nM and 60 nM, respectively. [2] |
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| Cell Data |
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| Assay |
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| In vivo | CEP-32496 exhibits good stability in mouse, dog, monkey, and human liver microsomal preparations with measured intrinsic clearance values of <23 (μL/min)/mg and t1/2 > 60 min in all assays. CEP-32496 (30 mg/kg, orally, BID) exhibits tumor stasis and a 40% incidence of partial tumor regressions (PRs) in Colo-205 xenograft mouse model, whereas the 100 mg/kg dose group exhibits both tumor stasis and an 80% incidence of PRs. CEP-32496 (30 mg/kg, orally, BID) leads to a 50% and 75% inhibition of normalized pMEK in tumor lysates at the 2 hours and 6 hours postdose time point, respectively, while a 55 mg/kg dose results in a 75% to 57% inhibition of pMEK at 2 hours through 10 hours post administration in Colo-205 xenograft mouse model. [1] CEP-32496 is orally bioavailable in multiple preclinical species (>95% in rats, dogs, and monkeys). CEP-32496 (100 mg/kg) results in inhibition of pMEK and pERK and sustained tumor stasis and regressions in BRAF(V600E) colon carcinoma xenografts in nude mice. [2] |
Protocol
| Kinase Assay:[1] |
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Binding assay: Kinases are produced displayed on T7 phage or by expression in HEK-293 cells and tagged with DNA. Binding reactions are performed at room temperature for 1 hour, and the fraction of kinase not bound to test compound is determined by capture with an immobilized affinity ligand and quantitation by quantitative PCR. Each kinase is tested individually against CEP-32496. Kd values are determined using eleven serial 3-fold dilutions and presented as mean values from experiments performed in duplicate. Variability between individual values is less than 2-fold. |
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| Cell Research:[1] |
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| Animal Research:[1] |
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Solubility (25°C)
| In vitro | DMSO | 9 mg/mL (17.39 mM) |
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| Water | Insoluble | |
| Ethanol | Insoluble | |
| In vivo | Add solvents to the product individually and in order(Data is from Selleck tests instead of citations): 15% Captisol For best results, use promptly after mixing. |
15 mg/mL |
* Please note that Selleck tests the solubility of all compounds in-house, and the actual solubility may differ slightly from published values. This is normal and is due to slight batch-to-batch variations.
Chemical Information
| Molecular Weight | 517.46 |
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| Formula | C24H22F3N5O5 |
| CAS No. | 1188910-76-0 |
| Storage |
powder in solvent |
| Synonyms | CEP-32496 |
| Smiles | CC(C)(C1=CC(=NO1)NC(=O)NC2=CC(=CC=C2)OC3=NC=NC4=CC(=C(C=C43)OC)OC)C(F)(F)F |
In vivo Formulation Calculator (Clear solution)
| Step 1: Enter information below (Recommended: An additional animal making an allowance for loss during the experiment) | ||||||||||
| Dosage | mg/kg |  |
Average weight of animals | g | |
Dosing volume per animal | ul | |
Number of animals | |
| Step 2: Enter the in vivo formulation () | ||||||||||
| % DMSO % % Tween 80 % ddH2O | ||||||||||
| CalculateReset | ||||||||||
Calculation results:
Working concentration： mg/ml；
Method for preparing DMSO master liquid: ： mg drug pre-dissolved in μL DMSO (Master liquid concentration mg/mL，)
Method for preparing in vivo formulation：Take μL DMSO master liquid, next addμL PEG300， mix and clarify, next addμL Tween 80，mix and clarify, next add μL ddH2O，mix and clarify.
1.Please make sure the liquid is clear before adding the next solvent.
2.Be sure to add the solvent(s) in order. You must ensure that the solution obtained, in the previous addition, is a clear solution before proceeding to add the next solvent. Physical methods such as vortex, ultrasound or hot water bath can be used to aid dissolving.
Bio Calculators
Molarity Calculator
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Dilution Calculator
Calculate the dilution required to prepare a stock solution. The Selleck dilution calculator is based on the following equation:
Concentration (start) x Volume (start) = Concentration (final) x Volume (final)
This equation is commonly abbreviated as: C1V1 = C2V2 ( Input Output )
* When preparing stock solutions always use the batch-specific molecular weight of the product found on the vial label and SDS / COA (available online).
Molecular Weight Calculator
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Molecular mass (molecular weight) is the mass of one molecule of a substance and is expressed in the unified atomic mass units (u). (1 u is equal to 1/12 the mass of one atom of carbon-12)
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Molarity Calculator
Tech Support
Answers to questions you may have can be found in the inhibitor handling instructions. Topics include how to prepare stock solutions, how to store inhibitors, and issues that need special attention for cell-based assays and animal experiments.
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