RXDX-105 (CEP-32496)
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MedKoo CAT#: 205903

CAS#: 1188910-76-0 (free base)

Description: Agerafenib, also known as RXDX-105, CEP-32496 and AC013773, is an orally available v-raf murine sarcoma viral oncogene homolog B1 (B-raf) serine/threonine protein kinase inhibitor with potential antineoplastic activity. CEP-32496 specifically and selectively inhibits the activity of the mutated form (V600E) of B-raf kinase. This inhibits the activation of the RAF/mitogen-activated protein kinase kinase (MEK)/extracellular signal-related kinase (ERK) signaling pathway and may result in a decrease in the proliferation of tumor cells expressing the mutated B-raf gene.


Chemical Structure

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RXDX-105 (CEP-32496)
CAS# 1188910-76-0 (free base)

Theoretical Analysis

MedKoo Cat#: 205903
Name: RXDX-105 (CEP-32496)
CAS#: 1188910-76-0 (free base)
Chemical Formula: C24H22F3N5O5
Exact Mass: 517.1573
Molecular Weight: 517.47
Elemental Analysis: C, 55.71; H, 4.29; F, 11.01; N, 13.53; O, 15.46

Price and Availability

Size Price Availability Quantity
10.0mg USD 150.0 Ready to ship
25.0mg USD 250.0 Ready to ship
50.0mg USD 450.0 Ready to ship
100.0mg USD 750.0 Ready to ship
200.0mg USD 1250.0 Ready to ship
500.0mg USD 2450.0 Ready to ship
1.0g USD 3450.0 2 Weeks
2.0g USD 5650.0 2 Weeks
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Synonym: RXDX-105; RXDX 105; RXDX105; CEP32496; CEP-32496; CEP 32496; AC013773; AC 013773; AC-013773. Agerafenib

IUPAC/Chemical Name: 1-(3-((6,7-dimethoxyquinazolin-4-yl)oxy)phenyl)-3-(5-(1,1,1-trifluoro-2-methylpropan-2-yl)isoxazol-3-yl)urea

InChi Key: DKNUPRMJNUQNHR-UHFFFAOYSA-N

InChi Code: InChI=1S/C24H22F3N5O5/c1-23(2,24(25,26)27)19-11-20(32-37-19)31-22(33)30-13-6-5-7-14(8-13)36-21-15-9-17(34-3)18(35-4)10-16(15)28-12-29-21/h5-12H,1-4H3,(H2,30,31,32,33)

SMILES Code: O=C(NC1=NOC(C(C)(C)C(F)(F)F)=C1)NC2=CC=CC(OC3=C4C=C(OC)C(OC)=CC4=NC=N3)=C2

Appearance: White to off-white solid powder

Purity: >98% (or refer to the Certificate of Analysis)

Shipping Condition: Shipped under ambient temperature as non-hazardous chemical. This product is stable enough for a few weeks during ordinary shipping and time spent in Customs.

Storage Condition: Dry, dark and at 0 - 4 C for short term (days to weeks) or -20 C for long term (months to years).

Solubility: Soluble in DMSO, not in water

Shelf Life: >2 years if stored properly

Drug Formulation: This drug may be formulated in DMSO

Stock Solution Storage: 0 - 4 C for short term (days to weeks), or -20 C for long term (months).

HS Tariff Code: 2934.99.9001

Biological target: Agerafenib (CEP-32496; RXDX-105) is an efficacious inhibitor of BRAFV600E with a Kd of 14 nM.
In vitro activity: RXDX-105 is a potent inhibitor of multiple kinases, including the RET and BRAF kinases (Figure 1) To investigate whether RXDX-105 is able to inhibit the RET kinase and the RAS-MAPK pathway in neuroblastoma cells, this study evaluated a panel of neuroblastoma cell lines for RET, MEK, and ERK expression and phosphorylation after 24 hours of treatment with RXDX-105. RET phosphorylation was inhibited with RXDX-105 treatment in a dose dependent manner, while levels of total RET remained relatively stable. RET phosphorylation was also increased after the addition of 5 μM 13-cis-retinoic acid, which was also inhibited by RXDX-105 (Figure 4). RXDX-105 treatment also resulted in significantly decreased MEK and ERK phosphorylation, while levels of total ERK remained the same or slightly increased (Figure 4, Supplementary Figure 1). Reference: Oncotarget. 2019 Oct 29; 10(59): 6323–6333. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6824878/
In vivo activity: Inhibition of MEK phosphorylation in BRAFV600E-positive subcutaneous Colo-205 tumor xenografts in nude mice was detected following administration of CEP-32496 (10, 30, and 55 mg/kg orally twice daily; Fig. 4A). CEP-32496 at 10 and 30 mg/kg resulted in significant (P < 0.03) inhibition of normalized pMEK in tumor lysates relative to vehicle controls at 2 and 6 hours but returned to baseline by 10 hours, whereas a 55 mg/kg dose resulted in a 75% to 57% (P < 0.03) inhibition of pMEK at 2 though 10-hour postadministration, with normalization to baseline by 24 hours. Reference: Mol Imaging. 2018 Jan-Dec;17:1536012118795952. https://mct.aacrjournals.org/content/11/4/930.long

Solubility Data

Solvent Max Conc. mg/mL Max Conc. mM
Solubility
DMSO 26.33 50.88
DMF 10.0 19.32
DMF:PBS (pH 7.2) (1:2) 0.3 0.58
Ethanol 2.0 3.86

Preparing Stock Solutions

The following data is based on the product molecular weight 517.47 Batch specific molecular weights may vary from batch to batch due to the degree of hydration, which will affect the solvent volumes required to prepare stock solutions.

Recalculate based on batch purity %
Concentration / Solvent Volume / Mass 1 mg 5 mg 10 mg
1 mM 1.15 mL 5.76 mL 11.51 mL
5 mM 0.23 mL 1.15 mL 2.3 mL
10 mM 0.12 mL 0.58 mL 1.15 mL
50 mM 0.02 mL 0.12 mL 0.23 mL
Formulation protocol: 1. Flynn SM, Lesperance J, Macias A, Phanhthilath N, Paul MR, Kim JW, Tamayo P, Zage PE. The multikinase inhibitor RXDX-105 is effective against neuroblastoma in vitro and in vivo. Oncotarget. 2019 Oct 29;10(59):6323-6333. doi: 10.18632/oncotarget.27259. PMID: 31695841; PMCID: PMC6824878. 2. James J, Ruggeri B, Armstrong RC, Rowbottom MW, Jones-Bolin S, Gunawardane RN, Dobrzanski P, Gardner MF, Zhao H, Cramer MD, Hunter K, Nepomuceno RR, Cheng M, Gitnick D, Yazdanian M, Insko DE, Ator MA, Apuy JL, Faraoni R, Dorsey BD, Williams M, Bhagwat SS, Holladay MW. CEP-32496: a novel orally active BRAF(V600E) inhibitor with selective cellular and in vivo antitumor activity. Mol Cancer Ther. 2012 Apr;11(4):930-41. doi: 10.1158/1535-7163.MCT-11-0645. Epub 2012 Feb 7. PMID: 22319199. 3. Jiang C, Xie L, Zhang Y, Fujinaga M, Mori W, Kurihara Y, Yamasaki T, Wang F, Zhang MR. Pharmacokinetic Evaluation of [11C]CEP-32496 in Nude Mice Bearing BRAFV600E Mutation-Induced Melanomas. Mol Imaging. 2018 Jan-Dec;17:1536012118795952. doi: 10.1177/1536012118795952. PMID: 30251592; PMCID: PMC6156206. 4. Li GG, Somwar R, Joseph J, Smith RS, Hayashi T, Martin L, Franovic A, Schairer A, Martin E, Riely GJ, Harris J, Yan S, Wei G, Oliver JW, Patel R, Multani P, Ladanyi M, Drilon A. Antitumor Activity of RXDX-105 in Multiple Cancer Types with RET Rearrangements or Mutations. Clin Cancer Res. 2017 Jun 15;23(12):2981-2990. doi: 10.1158/1078-0432.CCR-16-1887. Epub 2016 Dec 23. PMID: 28011461; PMCID: PMC5477238.
In vitro protocol: 1. Flynn SM, Lesperance J, Macias A, Phanhthilath N, Paul MR, Kim JW, Tamayo P, Zage PE. The multikinase inhibitor RXDX-105 is effective against neuroblastoma in vitro and in vivo. Oncotarget. 2019 Oct 29;10(59):6323-6333. doi: 10.18632/oncotarget.27259. PMID: 31695841; PMCID: PMC6824878. 2. James J, Ruggeri B, Armstrong RC, Rowbottom MW, Jones-Bolin S, Gunawardane RN, Dobrzanski P, Gardner MF, Zhao H, Cramer MD, Hunter K, Nepomuceno RR, Cheng M, Gitnick D, Yazdanian M, Insko DE, Ator MA, Apuy JL, Faraoni R, Dorsey BD, Williams M, Bhagwat SS, Holladay MW. CEP-32496: a novel orally active BRAF(V600E) inhibitor with selective cellular and in vivo antitumor activity. Mol Cancer Ther. 2012 Apr;11(4):930-41. doi: 10.1158/1535-7163.MCT-11-0645. Epub 2012 Feb 7. PMID: 22319199.
In vivo protocol: 1. Jiang C, Xie L, Zhang Y, Fujinaga M, Mori W, Kurihara Y, Yamasaki T, Wang F, Zhang MR. Pharmacokinetic Evaluation of [11C]CEP-32496 in Nude Mice Bearing BRAFV600E Mutation-Induced Melanomas. Mol Imaging. 2018 Jan-Dec;17:1536012118795952. doi: 10.1177/1536012118795952. PMID: 30251592; PMCID: PMC6156206. 2. Li GG, Somwar R, Joseph J, Smith RS, Hayashi T, Martin L, Franovic A, Schairer A, Martin E, Riely GJ, Harris J, Yan S, Wei G, Oliver JW, Patel R, Multani P, Ladanyi M, Drilon A. Antitumor Activity of RXDX-105 in Multiple Cancer Types with RET Rearrangements or Mutations. Clin Cancer Res. 2017 Jun 15;23(12):2981-2990. doi: 10.1158/1078-0432.CCR-16-1887. Epub 2016 Dec 23. PMID: 28011461; PMCID: PMC5477238.

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1: James J, Ruggeri B, Armstrong RC, Rowbottom MW, Jones-Bolin S, Gunawardane RN, Dobrzanski P, Gardner MF, Zhao H, Cramer MD, Hunter K, Nepomuceno RR, Cheng M, Gitnick D, Yazdanian M, Insko DE, Ator MA, Apuy JL, Faraoni R, Dorsey BD, Williams M, Bhagwat SS, Holladay MW. CEP-32496: a novel orally active BRAF(V600E) inhibitor with selective cellular and in vivo antitumor activity. Mol Cancer Ther. 2012 Apr;11(4):930-41. doi: 10.1158/1535-7163.MCT-11-0645. Epub 2012 Feb 7. PubMed PMID: 22319199.



Additional Information

Related CAS#
CAS#1188910-76-0 (free base)
CAS#1227678-26-3 ( HCl salt).