Vemurafenib | PLX-4032 | CAS#918504-65-1 | BRAF(V600E) Kinase Binder

MedKoo Cat#: 202271 | Name: Vemurafenib

Description:

WARNING: This product is for research use only, not for human or veterinary use.

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

Vemurafenib

CAS#918504-65-1

Theoretical Analysis

MedKoo Cat#: 202271

Name: Vemurafenib

CAS#: 918504-65-1

Chemical Formula: C23H18ClF2N3O3S

Exact Mass: 489.0726

Molecular Weight: 489.92

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
200mg	USD 150.00	Ready to ship
500mg	USD 250.00	Ready to ship
1g	USD 450.00	Ready to ship
2g	USD 750.00	Ready to ship
5g	USD 1,650.00	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 HoffmannÂ–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: ZELBORAFÂ™ 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.

Product Data

Product Data

Certificate of Analysis

View CoA: current batch, Lot#C9R12B04

View CoA: current batch, Lot#X7P08R09

QC Data

View QC data: current batch, Lot#X7P08R09

View QC data: current batch, Lot#C9R12B04

Safety Data Sheet (SDS)

View Safety Data Sheet (SDS)

Instruction

View handling instruction

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/

	Solvent	mg/mL	mM
Solubility
	DMSO	80.0	163.29

Note: There can be variations in solubility for the same chemical from different vendors or different batches from the same vendor. The following factors can affect the solubility of the same chemical: solvent used for crystallization, residual solvent content, polymorphism, salt versus free form, degree of hydration, solvent temperature. Please use the solubility data as a reference only. Warming and sonication will facilitate dissolving. Still have questions? Please contact our Technical Support scientists.

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.

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:

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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PMID: 39469641; PMCID: PMC11514068. 19: Jameleddine M, Harzallah N, Grati H, Odabachian Jebali MC, Chemli J, García Martí S, Soto N, Pichon-Riviere A, Hamouda C. INEAS's Cost-Effectiveness Analysis of Vemurafenib: Paving the Way for Value-Based Pricing in Tunisia. J Mark Access Health Policy. 2024 Oct 6;12(4):294-305. doi: 10.3390/jmahp12040023. PMID: 39464179; PMCID: PMC11503406. 20: Yamauchi M, Sakai A, Ebisumoto K, Iijima H, Teramura T, Yamazaki A, Yanagiya R, Yamamoto A, Ota Y, Ashida H, Kobayashi N, Okami K. Combination therapy with BRAF and MEK inhibitors for anaplastic thyroid cancer: A report of two cases. Auris Nasus Larynx. 2024 Dec;51(6):1003-1008. doi: 10.1016/j.anl.2024.10.002. Epub 2024 Oct 23. PMID: 39447455.