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Agerafenib HCl, the hydrochloride salt of Agerafenib (RXDX-105; CEP-32496; AC-01377), is a potent and orally bioactive inhibitor of BRAFV600E and c-Raf with potential antitumor activity. It inhibits BRAFV600E with Kd values of 14 nM nM and 39 nM, respectively. Agerafenib showed little or no inhibition against other kinases such as MEK-1, MEK-2, ERK-1 and ERK-2.
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| ln Vitro |
High potency against multiple BRAFV600E-dependent cell lines is demonstrated by Agerafenib (CEP-32496), which also demonstrates preferential cytotoxicity towards tumor cell lines expressing mutant BRAFV600E in contrast to those having wild-type BRAF. In the proliferation experiment, agerafenib (CEP-32496) demonstrates strong binding (BRAFV600E Kd=14 nM) and cellular activity (pMEK IC50=82 nM and A375 proliferation IC50=78 nM). With determined IC50 values greater than 10 μM against the CYP1A2, CYP2C9, CYP2D6, and CYP3A4 isoforms and an IC50=3.4 μM against CYP2C19, CEP-32496 also demonstrates a favorable CYP450 inhibition profile[1].
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| ln Vivo |
Agerafenib (CEP-32496) significantly inhibits pMEK in tumor cell lysates when given orally to mice with Colo-205 tumor xenografts. Agerafenib (CEP-32496), for example, exhibits a 50 and 75% inhibition of normalized pMEK in tumor lysates at the 2 and 6 h postdose time point, respectively (p<0.03), following a single 30 mg/kg (po) dose. Conversely, a 55 mg/kg (po) dose produced a 75% to 57% (p <0.03) inhibition of pMEK at the 2 through 10 h post administration, with a 24 h normalization to baseline. The PK profile of agerafenib (CEP-32496) administration in mice, dogs, and cynomolgus monkeys is remarkable. beagle dogs (single dose of 1 mg/kg iv and 10 mg/kg po) produces good bioavailability (%F=100) and low clearance (CL=5.0 (mL/min)/kg). Similar to this, Agerafenib (CEP-32496) administration results in high oral exposure in cynomolgus monkeys because of its good bioavailability (% F=100) and poor clearance (CL=6.7 mL/min/kg) at a single dosage of 1 mg/kg po and 1 mg/kg iv[1].
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| References |
[1]. Rowbottom MW, et al. Identification of 1-(3-(6,7-dimethoxyquinazolin-4-yloxy)phenyl)-3-(5-(1,1,1-trifluoro-2-methylpropan-2-yl)isoxazol-3-yl)urea hydrochloride (CEP-32496), a highly potent and orally efficacious inhibitor of V-RAF murine sarcoma viral on
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| Molecular Formula |
C₂₄H₂₃CLF₃N₅O₅
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| Molecular Weight |
553.92
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| CAS # |
1227678-26-3
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| Related CAS # |
Agerafenib;1188910-76-0
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| SMILES |
O=C(NC1=NOC(C(C)(C)C(F)(F)F)=C1)NC2=CC=CC(OC3=C(C=C(OC)C(OC)=C4)C4=NC=N3)=C2.[H]Cl
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| Synonyms |
CEP-32496 hydrochlorideRXDX-105CEP-32496AC-01377
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| Storage |
Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month |
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Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
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| Solubility (In Vivo) |
Note: Listed below are some common formulations that may be used to formulate products with low water solubility (e.g. < 1 mg/mL), you may test these formulations using a minute amount of products to avoid loss of samples.
Injection Formulations
Injection Formulation 1: DMSO : Tween 80： Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution → 50 μL Tween 80 → 850 μL Saline)(e.g. IP/IV/IM/SC) *Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH ₂ O to obtain a clear solution. Injection Formulation 2: DMSO : PEG300 ：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL DMSO → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline) Injection Formulation 3: DMSO : Corn oil = 10 : 90 (i.e. 100 μL DMSO → 900 μL Corn oil) Example: Take the Injection Formulation 3 (DMSO : Corn oil = 10 : 90) as an example, if 1 mL of 2.5 mg/mL working solution is to be prepared, you can take 100 μL 25 mg/mL DMSO stock solution and add to 900 μL corn oil, mix well to obtain a clear or suspension solution (2.5 mg/mL, ready for use in animals). View More
Injection Formulation 4: DMSO : 20% SBE-β-CD in saline = 10 : 90 [i.e. 100 μL DMSO → 900 μL (20% SBE-β-CD in saline)] Oral Formulations
Oral Formulation 1: Suspend in 0.5% CMC Na (carboxymethylcellulose sodium) Oral Formulation 2: Suspend in 0.5% Carboxymethyl cellulose Example: Take the Oral Formulation 1 (Suspend in 0.5% CMC Na) as an example, if 100 mL of 2.5 mg/mL working solution is to be prepared, you can first prepare 0.5% CMC Na solution by measuring 0.5 g CMC Na and dissolve it in 100 mL ddH2O to obtain a clear solution; then add 250 mg of the product to 100 mL 0.5% CMC Na solution, to make the suspension solution (2.5 mg/mL, ready for use in animals). View More
Oral Formulation 3: Dissolved in PEG400 (Please use freshly prepared in vivo formulations for optimal results.) |
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| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 1.8053 mL | 9.0266 mL | 18.0531 mL | |
| 5 mM | 0.3611 mL | 1.8053 mL | 3.6106 mL | |
| 10 mM | 0.1805 mL | 0.9027 mL | 1.8053 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.
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