CEP-32496(RXDX-105)

Catalog No.S8015

CEP-32496(RXDX-105) Chemical Structure

Molecular Weight(MW): 517.46

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, PDGFRβ and VEGFR2, respectively; insignificant affinity for MEK-1, MEK-2, ERK-1 and ERK-2. Phase 1/2.

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In DMSO USD 560 In stock
USD 270 In stock
USD 370 In stock
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Biological Activity

Description 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, PDGFRβ and VEGFR2, respectively; insignificant affinity for MEK-1, MEK-2, ERK-1 and ERK-2. Phase 1/2.
Features High binding affinity for both BRAF (V600E) mutation and related c-Raf, but no significant affinity for other kinases of MAPK pathway.
Targets
c-Kit [1] LCK [1] PDGFRβ [1] RET [1] Abl1 [1]
2 nM(Kd) 2 nM(Kd) 2 nM(Kd) 2 nM(Kd) 3 nM(Kd)
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]
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.
Cell Research:[1]
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  • Cell lines: A375 cell lines
  • Concentrations: 78 nM
  • Incubation Time: 72 hours
  • Method: Cells are seeded at 104 cells per well in DMEM with 10% fetal calf serum and allowed to attach. The cells are washed with PBS and switched to DMEM with 0.5% of serum and incubated overnight. CEP-32496 is then added at various concentrations with a final DMSO concentration of 0.5% and incubated for 72 h. At the end of incubation, a Cell Titer Blue is added per instructions, and incubation is continued for 3 hours. Remaining viable cells are quantified by measuring the strength of the fluorescence signal using SoftMax Pro (excitation at 560 nm and emission at 590 nm). IC50 values are derived using a 9-point curve fitted with Igor Pro and are presented as mean values from experiments performed in duplicate. Variability between individual values is less than 2-fold.
    (Only for Reference)
Animal Research:[1]
+ Expand
  • Animal Models: Colo-205 xenograft mouse model
  • Formulation: 22% HPβCD
  • Dosages: 100 mg/kg
  • Administration: oral gavage
    (Only for Reference)

Solubility (25°C)

In vitro DMSO 9 mg/mL (17.39 mM)
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
Formula

C24H22F3N5O5
CAS No. 1188910-76-0
Storage powder
in solvent
Synonyms N/A

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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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Raf Signaling Pathway Map

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Cell Lines Assay Type Concentration Incubation Time Formulation Activity Description PMID