Home MAPK Raf inhibitor - CSF-1R inhibitor - c-Kit inhibitor - PDGFR inhibitor - c-RET inhibitor Agerafenib (CEP-32496) For research use only.

Agerafenib (CEP-32496)

Synonyms: RXDX-105

Agerafenib (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.

Agerafenib (CEP-32496) Chemical Structure

Agerafenib (CEP-32496) Chemical Structure

CAS: 1188910-76-0

Selleck's Agerafenib (CEP-32496) has been cited by 6 publications

Purity & Quality Control

Batch: S801501 DMSO] 9 mg/mL] false] Water] Insoluble] false] Ethanol] Insoluble] false Purity: 99.19%
99.19

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Cell Data

Cell Lines Assay Type Concentration Incubation Time Formulation Activity Description PMID
HEK293 Function assay 1 hr Inhibition of LCK in human HEK293 cells after 1 hr by competition binding assay, Kd=0.002μM. 22168626
HEK293 Function assay 1 hr Inhibition of PDGFRbeta in human HEK293 cells after 1 hr by competition binding assay, Kd=0.002μM. 22168626
HEK293 Function assay 1 hr Inhibition of cKit in human HEK293 cells after 1 hr by competition binding assay, Kd=0.002μM. 22168626
HEK293 Function assay 1 hr Inhibition of Ret in human HEK293 cells after 1 hr by competition binding assay, Kd=0.002μM. 22168626
HEK293 Function assay 1 hr Inhibition of Abl1 in human HEK293 cells after 1 hr by competition binding assay, Kd=0.003μM. 22168626
HEK293 Function assay 1 hr Inhibition of VEGFR2 in human HEK293 cells after 1 hr by competition binding assay, Kd=0.008μM. 22168626
HEK293 Function assay 1 hr Inhibition of CSF1R in human HEK293 cells after 1 hr by competition binding assay, Kd=0.009μM. 22168626
HEK293 Function assay 1 hr Inhibition of EPHA2 in human HEK293 cells after 1 hr by competition binding assay, Kd=0.014μM. 22168626
HEK293 Function assay 1 hr Inhibition of BRAF V600E mutant in human HEK293 cells after 1 hr by competition binding assay, Kd=0.014μM. 22168626
HEK293 Function assay 1 hr Inhibition of EGFR in human HEK293 cells after 1 hr by competition binding assay, Kd=0.022μM. 22168626
HEK293 Function assay 1 hr Inhibition of wild type BRAF in human HEK293 cells after 1 hr by competition binding assay, Kd=0.036μM. 22168626
COLO205 Cytotoxicity assay 72 hrs Cytotoxicity against human COLO205 cells expressing BRAF V600E mutant after 72 hrs by cell titer blue assay, EC50=0.036μM. 22168626
HEK293 Function assay 1 hr Inhibition of CRAF in human HEK293 cells after 1 hr by competition binding assay, Kd=0.039μM. 22168626
A375 Cytotoxicity assay 72 hrs Cytotoxicity against human A375 cells expressing BRAF V600E mutant after 72 hrs by cell titer blue assay, IC50=0.078μM. 22168626
A375 Function assay 2 hrs Inhibition of BRAF V600E mutant-mediated MEK phosphorylation in human A375 cells after 2 hrs, IC50=0.082μM. 22168626
HCC827 Function assay Displacement of [3H]-cyclopamine from SMO V404M mutant in gefitinib resistant human HCC827 cells by scintillation counting, Ki=0.1878μM. 28787156
COLO679 Cytotoxicity assay 72 hrs Cytotoxicity against human COLO679 cells expressing BRAF V600E mutant after 72 hrs by cell titer blue assay, EC50=0.211μM. 22168626
HT144 Cytotoxicity assay 72 hrs Cytotoxicity against human HT144 cells expressing BRAF V600E mutant after 72 hrs by cell titer blue assay, EC50=0.228μM. 22168626
SK-MEL-28 Cytotoxicity assay 72 hrs Cytotoxicity against human SK-MEL-28 cells expressing BRAF V600E mutant after 72 hrs by cell titer blue assay, EC50=0.454μM. 22168626
HEK293 Function assay 1 hr Inhibition of cMET in human HEK293 cells after 1 hr by competition binding assay, Kd=0.513μM. 22168626
HCT116 Cytotoxicity assay 72 hrs Cytotoxicity against human HCT116 cells expressing wild type BRAF after 72 hrs by cell titer blue assay, EC50=0.669μM. 22168626
Hs578T Cytotoxicity assay 72 hrs Cytotoxicity against human Hs578T cells expressing wild type BRAF after 72 hrs by cell titer blue assay, EC50=2.736μM. 22168626
DU145 Cytotoxicity assay 72 hrs Cytotoxicity against human DU145 cells expressing wild type BRAF after 72 hrs by cell titer blue assay, EC50=2.911μM. 22168626
HEK293 Function assay 1 hr Inhibition of JAK2 in human HEK293 cells after 1 hr by competition binding assay, Kd=4.7μM. 22168626
PC3 Cytotoxicity assay 72 hrs Cytotoxicity against human PC3 cells expressing wild type BRAF after 72 hrs by cell titer blue assay, EC50=6.257μM. 22168626
LNCAP Cytotoxicity assay 72 hrs Cytotoxicity against human LNCAP cells expressing wild type BRAF after 72 hrs by cell titer blue assay, EC50=6.631μM. 22168626
HEK293 Function assay 1 hr Inhibition of MEK1 in human HEK293 cells after 1 hr by competition binding assay, Kd=7.1μM. 22168626
HEK293 Function assay 1 hr Inhibition of MEK2 in human HEK293 cells after 1 hr by competition binding assay, Kd=8.3μM. 22168626
COLO205 Antitumor assay 10 mg/kg 14 days Antitumor activity against human COLO205 cells xenografted in athymic nude mouse at 10 mg/kg, po bid for 14 days 22168626
COLO205 Antitumor assay 30 mg/kg 14 days Antitumor activity against human COLO205 cells xenografted in athymic nude mouse at 30 mg/kg, po bid for 14 days 22168626
COLO205 Antitumor assay 100 mg/kg 14 days Antitumor activity against human COLO205 cells xenografted in athymic nude mouse at 100 mg/kg, po bid for 14 days 22168626
Click to View More Cell Line Experimental Data

Biological Activity

Description Agerafenib (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.
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] Click to View More Targets
2 nM(Kd) 2 nM(Kd) 2 nM(Kd) 2 nM(Kd) 3 nM(Kd)
In vitro
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]
Kinase Assay 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 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.
Experimental Result Images Methods Biomarkers Images PMID
Growth inhibition assay Cell viability 31695841
Western blot p-RET / RET / p-PLCγ / PLCγ / p-ERK / ERK / p-MEK / MEK 28011461
In Vivo
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]
Animal Research Animal Models Colo-205 xenograft mouse model
Dosages 100 mg/kg
Administration oral gavage

Chemical lnformation & Solubility

Molecular Weight 517.46 Formula

C24H22F3N5O5
CAS No. 1188910-76-0 SDF Download Agerafenib (CEP-32496) SDF
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
Storage (From the date of receipt)

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Batch:

DMSO : 9 mg/mL ( (17.39 mM)； Moisture-absorbing DMSO reduces solubility. Please use fresh DMSO.)

Water : Insoluble

Ethanol : Insoluble


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