Agerafenib (RXDX-105)

Name: Agerafenib (RXDX-105)
Brand: Selleck Chemicals
SKU: S8015
Rating: 5 (5 reviews)

For research use only.

Catalog No.S8015 Synonyms: CEP-32496

5 publications

Agerafenib (RXDX-105) Chemical Structure

CAS No. 1188910-76-0

Agerafenib (RXDX-105, CEP-32496) is a highly potent inhibitor of BRAF(V600E/WT) and c-Raf with K_d 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.

Selleck's Agerafenib (RXDX-105) has been cited by 5 publications

Dis Model Mech, 2020, dmm.047779

PubMed: 33318047 ( click the link to review the publication )

Photodermatol Photoimmunol Photomed, 2019, 10.1111/phpp.12520

PubMed: 31618797 ( click the link to review the publication )

Exp Gerontol, 2019, 126:110691

PubMed: 31421186 ( click the link to review the publication )

Cancer Immunol Res, 2019,

PubMed: 31540894 ( click the link to review the publication )

Nat Biomed Eng, 2018, 2(8):578-588

PubMed: 31015631 ( click the link to review the publication )

Purity & Quality Control

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Biological Activity

Description

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]	View More
2 nM(Kd)	2 nM(Kd)	2 nM(Kd)	2 nM(Kd)	3 nM(Kd)	View More

In vitro

CEP-32496 inhibits A375 cell (BRAF^V600E) 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]

Assay

Methods	Test Index	PMID
Growth inhibition assay	Cell viability; PubMed: 31695841 Oncotarget Cell viability was assessed with alamarBlue assays performed after 72 hours of incubation with RXDX-105, and dose-response curves (left) and calculated IC50 values (right) are shown.	31695841
Western blot	p-RET / RET / p-PLCγ / PLCγ / p-ERK / ERK / p-MEK / MEK ; PubMed: 28011461 Clin Cancer Res Inhibition of phosphorylation of RET and downstream pathways by RXDX-105 in TT cells (RET C634W).	28011461

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 t_1/2 > 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]	- Collapse 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]	- Collapse 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]	- Collapse Animal Models: Colo-205 xenograft mouse model Dosages: 100 mg/kg Administration: oral gavage (Only for Reference)

References

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 Download Agerafenib (RXDX-105) SDF

Molecular Weight	517.46
Formula	C₂₄H₂₂F₃N₅O₅
CAS No.	1188910-76-0
Storage	3 years-20°C powder 2 years-80°C 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

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Method for preparing DMSO master liquid: ： mg drug pre-dissolved in μL DMSO (Master liquid 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 master liquid, next addμL PEG300， mix and clarify, next addμL Tween 80，mix and clarify, next add μL ddH₂O，mix and clarify.

Note：1.Please make sure the liquid is clear before adding the next solvent.
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Bio Calculators

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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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Agerafenib (RXDX-105)