Vemurafenib
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MedKoo CAT#: 202271

CAS#: 918504-65-1

Description: Vemurafenib, also known as PLX4032, RG7204 or RO5185426, is an orally bioavailable, ATP-competitive, small-molecule inhibitor of BRAF(V600E) kinase with potential antineoplastic activity. Vemurafenib received FDA approval for the treatment of late-stage melanoma on August 17, 2011. Vemurafenib selectively binds to the ATP-binding site of BRAF(V600E) kinase and inhibits its activity, which may result in an inhibition of an over-activated MAPK signaling pathway downstream in BRAF(V600E) kinase-expressing tumor cells and a reduction in tumor cell proliferation.

Chemical Structure

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Vemurafenib
CAS# 918504-65-1
Product data Instruction

Theoretical Analysis

MedKoo Cat#: 202271
Name: Vemurafenib
CAS#: 918504-65-1
Chemical Formula: C23H18ClF2N3O3S
Exact Mass: 489.07
Molecular Weight: 489.920
Elemental Analysis: C, 56.39; H, 3.70; Cl, 7.24; F, 7.76; N, 8.58; O, 9.80; S, 6.54

Price and Availability

Size Price Availability Quantity
200mg USD 150 Ready to ship
500mg USD 250 Ready to ship
1g USD 450 Ready to ship
2g USD 750 Ready to ship
5g USD 1650 Ready to ship
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Related CAS #: 918505-61-0 (analog)   918504-65-1    

Synonym: PLX4032; PLX 4032; PLX-4032; RG7204 ; RG7204 ; RG 7204 ; RO5185426; RO 5185426 RO5185426 Vemurafenib; Brand name: Zelboraf

IUPAC/Chemical Name: N-(3-(5-(4-chlorophenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluorophenyl)propane-1-sulfonamide

InChi Key: GPXBXXGIAQBQNI-UHFFFAOYSA-N

InChi Code: InChI=1S/C23H18ClF2N3O3S/c1-2-9-33(31,32)29-19-8-7-18(25)20(21(19)26)22(30)17-12-28-23-16(17)10-14(11-27-23)13-3-5-15(24)6-4-13/h3-8,10-12,29H,2,9H2,1H3,(H,27,28)

SMILES Code: CCCS(=O)(NC1=CC=C(F)C(C(C2=CNC3=NC=C(C4=CC=C(Cl)C=C4)C=C32)=O)=C1F)=O

Appearance: White to off-white crystalline solid

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

More Info: Vemurafenib is developed by Plexxikon (now part of the Daiichi Sankyo group) and Hoffmann–La Roche for the treatment of late-stage melanoma. Vemurafenib received FDA approval for the treatment of late-stage melanoma on August 17, 2011.      Drug information ZELBORAF (vemurafenib) is a kinase inhibitor available as 240 mg tablets for oral use. Vemurafenib has the chemical name propane-1-sulfonic acid {3-[5-(4-chlorophenyl)-lH-pyrrolo[2,3-b]pyridine-3-carbonyl]-2,4-difluoro-phenyl}-amide. It has the molecular formula C23H18ClF2N3O3S and a molecular weight of 489.9. Vemurafenib is a white to off-white crystalline solid. It is practically insoluble in aqueous media. Tablets of ZELBORAF are for oral administration. Each tablet contains 240 mg of vemurafenib. The inactive ingredients of ZELBORAF are: Tablet Core: hypromellose acetate succinate, croscarmellose sodium, colloidal silicon dioxide, magnesium stearate, and hydroxypropyl cellulose. Coating: pinkish white: poly(vinyl alcohol), titanium dioxide, polyethylene glycol 3350, talc, and iron oxide red.  Indication: ZELBORAF™ is indicated for the treatment of patients with unresectable or metastatic melanoma with BRAFV600E mutation as detected by an FDA-approved test. Limitation of Use: ZELBORAF is not recommended for use in patients with wild-type BRAF melanoma.     Mechanism of Action: Vemurafenib is a low molecular weight, orally available, inhibitor of some mutated forms of BRAF serine-threonine kinase, including BRAFV600E. Vemurafenib also inhibits other kinases in vitro such as CRAF, ARAF, wild-type BRAF, SRMS, ACK1, MAP4K5 and FOR at similar concentrations. Some mutations in the BRAF gene including V600E result in constitutively activated BRAF proteins, which can cause cell proliferation in the absence of growth factors that would normally be required for proliferation. Vemurafenib has anti-tumor effects in cellular and animal models of melanomas with mutated BRAFV600E.  Pharmacokinetics: The pharmacokinetics of vemurafenib were determined in patients with BRAF mutation-positive metastatic melanoma following 15 days of dosing at 960 mg twice daily with dosing approximately 12 hours apart. The population pharmacokinetic analysis pooled data from 458 patients. A one-compartment disposition model with first-order absorption and first-order elimination adequately describes the vemurafenib concentration-time profile. At steady state, vemurafenib exhibits linear pharmacokinetics within the 240 mg to 960 mg dose range.     

Biological target: Vemurafenib (PLX4032) is a first-in-class, selective, potent inhibitor of B-RAF kinase, with IC50s of 31 and 48 nM for RAFV600E and c-RAF-1, respectively. Vemurafenib induces cell autophagy.
In vitro activity: The present study aimed to examine the effect of the antioxidants coenzyme Q10 (CoQ10) and β-carotene on melanoma cell growth and invasiveness and on the cytotoxicity of vemurafenib against both vemurafenib-sensitive (SK-MEL-28) and vemurafenib-resistant (A2058) human malignant melanoma cell lines.. In the SK-MEL-28 cell line, which is vemurafenib sensitive, CoQ10 decreased the cell viability and displayed cytotoxicity at 5 and 10 µM, but did not affect the cytotoxicity of PLX (Fig. 1A). In A2058, which is a vemurafenib-resistant cell line, CoQ10 did not display cytotoxicity (Fig. 1B). However, CoQ10 increased the cytotoxicity of PLX at 1, 5 and 10 µM (Fig. 1B). In both SK-MEL-28 and A2058 cell lines, β-carotene did not display cytotoxicity (Fig. 1C and D). However, β-carotene alleviated the cytotoxicity of PLX in both cell lines (Fig. 1C and D).Wound-healing and Transwell assay demonstrated that β-carotene alleviated the cytotoxicity of vemurafenib and mitigated the inhibitory effect of vemurafenib on cell migration and invasion. Both CoQ10 and β-carotene protected melanoma cells from undergoing apoptosis induced by vemurafenib. Immunoblotting demonstrated that β-carotene at physiological concentration worked synergistically with vemurafenib to suppress the Ras-Raf-Mek-Erk intracellular signaling pathway. The intake of β-carotene may decrease the therapeutic effect of vemurafenib. Oncol Lett. 2021 Mar; 21(3): 208.Published online 2021 Jan 14. doi: 10.3892/ol.2021.12469 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7816282/
In vivo activity: To test whether transcriptional adaptation can drive melanoma progression, zebrafish mitfa:BRAFV600E;tp53-/- models were used, in which malignant progression is characterized by minimal genetic evolution. SATB2 binds and activates neural crest-regulators, including pdgfab and snai2. The transcriptional program induced by SATB2 overlaps with known MITFlowAXLhigh and AQP1+NGFR1high drug-resistant states and functionally drives enhanced tumor propagation and resistance to Vemurafenib in vivo. To test whether the SATB2-induced program confers resistance to MAPK pathway inhibition, we utilized an established in vivo drug treatment assay where primary zebrafish melanoma are allotransplanted in irradiated casper recipients and administered a BRAFi (Vemurafenib 100 mg/kg) daily via oral gavage starting at day 10 post transplant (Figure 5D). Specifically, it was showed to induce resistance across four human melanoma cell lines to BRAF inhibitor PLX4720, which is the progenitor compound of FDA-approved BRAF inhibitor Vemurafenib (PLX4032). It was sought to functionally validate SATB2 as a resistance driver by conducting in vivo limiting dilution transplants and drug treatments with Vemurafenib using established assays in zebrafish allografts and showed MCR:SATB2 tumors to have increased tumor propagating potential (Figure 5A–C), and primary resistance to Vemurafenib treatment in vivo (Figure 5D–F). Analysis of tumor growth by measuring tumor area with digital calipers after 2 weeks (day 24 post-transplant) of treatment with Vemurafenib or a DMSO vehicle control showed a complete lack of response in MCR:SATB2 compared to Vemurafenib sensitive MCR:EGFP tumors (Figure 5E–F) (MCR:EGFP BRAFi vs. MCR:SATB2 BRAFi 2-tailed t-test p<0.0001****). This data functionally validates SATB2 as a driver of enhanced tumor propagation and drug resistance in vivo. In summary, the work identifies SATB2 as a driver of invasion and resistance to Vemurafenib treatment in melanoma. eLife. 2021; 10: e64370.Published online 2021 Feb 2. doi: 10.7554/eLife.64370 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7880683/

Solubility Data

Solvent Max Conc. mg/mL Max Conc. mM
Solubility
DMSO 80.0 163.29

Preparing Stock Solutions

The following data is based on the product molecular weight 489.92 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. Chang X, Zhang T, Wang Q, Rathore MG, Reddy K, Chen H, Shin SH, Ma WY, Bode AM, Dong Z. HI-511 overcomes melanoma drug resistance via targeting AURKB and BRAF V600E. Theranostics. 2020 Aug 1;10(21):9721-9740. doi: 10.7150/thno.44342. PMID: 32863956; PMCID: PMC7449901. 2. Hu C, Huang Y, Luo P, Yang Y. Effect of antioxidants coenzyme Q10 and β-carotene on the cytotoxicity of vemurafenib against human malignant melanoma. Oncol Lett. 2021 Mar;21(3):208. doi: 10.3892/ol.2021.12469. Epub 2021 Jan 14. PMID: 33574947; PMCID: PMC7816282. 3.Fazio M, van Rooijen E, Dang M, van de Hoek G, Ablain J, Mito JK, Yang S, Thomas A, Michael J, Fabo T, Modhurima R, Pessina P, Kaufman CK, Zhou Y, White RM, Zon LI. SATB2 induction of a neural crest mesenchyme-like program drives melanoma invasion and drug resistance. Elife. 2021 Feb 2;10:e64370. doi: 10.7554/eLife.64370. PMID: 33527896; PMCID: PMC7880683. 4.Chang X, Zhang T, Wang Q, Rathore MG, Reddy K, Chen H, Shin SH, Ma WY, Bode AM, Dong Z. HI-511 overcomes melanoma drug resistance via targeting AURKB and BRAF V600E. Theranostics. 2020 Aug 1;10(21):9721-9740. doi: 10.7150/thno.44342. PMID: 32863956; PMCID: PMC7449901.
In vitro protocol: 1. Chang X, Zhang T, Wang Q, Rathore MG, Reddy K, Chen H, Shin SH, Ma WY, Bode AM, Dong Z. HI-511 overcomes melanoma drug resistance via targeting AURKB and BRAF V600E. Theranostics. 2020 Aug 1;10(21):9721-9740. doi: 10.7150/thno.44342. PMID: 32863956; PMCID: PMC7449901. 2. Hu C, Huang Y, Luo P, Yang Y. Effect of antioxidants coenzyme Q10 and β-carotene on the cytotoxicity of vemurafenib against human malignant melanoma. Oncol Lett. 2021 Mar;21(3):208. doi: 10.3892/ol.2021.12469. Epub 2021 Jan 14. PMID: 33574947; PMCID: PMC7816282.
In vivo protocol: 1. Fazio M, van Rooijen E, Dang M, van de Hoek G, Ablain J, Mito JK, Yang S, Thomas A, Michael J, Fabo T, Modhurima R, Pessina P, Kaufman CK, Zhou Y, White RM, Zon LI. SATB2 induction of a neural crest mesenchyme-like program drives melanoma invasion and drug resistance. Elife. 2021 Feb 2;10:e64370. doi: 10.7554/eLife.64370. PMID: 33527896; PMCID: PMC7880683. 2. Chang X, Zhang T, Wang Q, Rathore MG, Reddy K, Chen H, Shin SH, Ma WY, Bode AM, Dong Z. HI-511 overcomes melanoma drug resistance via targeting AURKB and BRAF V600E. Theranostics. 2020 Aug 1;10(21):9721-9740. doi: 10.7150/thno.44342. PMID: 32863956; PMCID: PMC7449901.

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1: Pellowska M, Merk D, Schubert-Zsilavecz M. Advances in personalized medicine - medicinal chemistry and pharmacology of vemurafenib and ivacaftor. Pharmazie. 2013 Jul;68(7):484-91. Review. PubMed PMID: 23923627.

2: Banaszynski M, Kolesar JM. Vemurafenib and ipilimumab: new agents for metastatic melanoma. Am J Health Syst Pharm. 2013 Jul 15;70(14):1205-10. doi: 10.2146/ajhp120260. Review. PubMed PMID: 23820456.

3: Liszkay G. [Vemurafenib (Zelboraf) in the therapy of melanoma]. Magy Onkol. 2013 Jun;57(2):110-3. doi: MagyOnkol.2013.57.2.110. Epub 2013 May 14. Review. Hungarian. PubMed PMID: 23795356.

4: Shaw HM, Nathan PD. Vemurafenib in melanoma. Expert Rev Anticancer Ther. 2013 May;13(5):513-22. doi: 10.1586/era.13.24. Review. PubMed PMID: 23617343.

5: Gonzalez D, Fearfield L, Nathan P, Tanière P, Wallace A, Brown E, Harwood C, Marsden J, Whittaker S. BRAF mutation testing algorithm for vemurafenib treatment in melanoma: recommendations from an expert panel. Br J Dermatol. 2013 Apr;168(4):700-7. doi: 10.1111/bjd.12248. Review. PubMed PMID: 23360189.

6: Sharma A, Shah SR, Illum H, Dowell J. Vemurafenib: targeted inhibition of mutated BRAF for treatment of advanced melanoma and its potential in other malignancies. Drugs. 2012 Dec 3;72(17):2207-22. doi: 10.2165/11640870-000000000-00000. Review. PubMed PMID: 23116250.

7: Jordan EJ, Kelly CM. Vemurafenib for the treatment of melanoma. Expert Opin Pharmacother. 2012 Dec;13(17):2533-43. doi: 10.1517/14656566.2012.737780. Epub 2012 Oct 24. Review. PubMed PMID: 23094782.

8: Bollag G, Tsai J, Zhang J, Zhang C, Ibrahim P, Nolop K, Hirth P. Vemurafenib: the first drug approved for BRAF-mutant cancer. Nat Rev Drug Discov. 2012 Nov;11(11):873-86. doi: 10.1038/nrd3847. Epub 2012 Oct 12. Review. PubMed PMID: 23060265.

9: Keating GM. Vemurafenib: in unresectable or metastatic melanoma. BioDrugs. 2012 Oct 1;26(5):325-34. doi: 10.2165/11209860-000000000-00000. Review. PubMed PMID: 22946753.

10: Boyd KP, Vincent B, Andea A, Conry RM, Hughey LC. Nonmalignant cutaneous findings associated with vemurafenib use in patients with metastatic melanoma. J Am Acad Dermatol. 2012 Dec;67(6):1375-9. doi: 10.1016/j.jaad.2012.06.045. Epub 2012 Aug 30. Review. PubMed PMID: 22940405.