Vemurafenib (PLX4032, RG7204)

Vemurafenib (PLX4032, RG7204) is a novel and potent inhibitor of B-RafV600E with IC50 of 31 nM.

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Vemurafenib (PLX4032, RG7204) Chemical Structure

Vemurafenib (PLX4032, RG7204) Chemical Structure
Molecular Weight: 489.92

Validation & Quality Control

Product Citations(46)

Customer Reviews(9)

Quality Control & MSDS

Related Compound Libraries

Vemurafenib (PLX4032, RG7204) is available in the following compound libraries:

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  • FDA-approved Inhibitor

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Product Information

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  • Vemurafenib (PLX4032, RG7204) Mechanism
  • Combination Therapy
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Product Description

Biological Activity

Description Vemurafenib (PLX4032, RG7204) is a novel and potent inhibitor of B-RafV600E with IC50 of 31 nM.
Targets SRMS [1] ACK1 [1] B-Raf (V600E) [1] C-Raf [1] MAP4K5 (KHS1) [1]

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IC50 18 nM 19 nM 31 nM 48 nM 51 nM
In vitro PLX4032 inhibits B-RAFV600E, C-RAF, as well as wildtype B-RAF, with IC50 of 31 nM, 48 nM and 100 nM, respectively. PLX4032 also inhibits several non-RAF kinases, including ACK1, KHS1, and SRMS, with IC50 of 18 nM to 51 nM. [1] In melanoma cell lines, the inhibitory effect by PLX4032 depends on B-RAF mutational status, because PLX4032 potently inhibits those harboring B-RAF V600 mutants, including V600E, V600D, V600K, and V600R, but not wildtype or other mutants. The IC50 values of PLX4032 on these cells, including MALME-3M, Colo829, Colo38, A375, SK-MEL28, and A2058, ranges from 20 nM to 1 μM. In these cells, PLX4032 (0.1 μM to 30 μM) also inhibits the phosphorylation of both MEK1/2 and ERK1/2. [2] PLX4032 is highly effective in the treatment of melanoma, for its ability of inhibiting B-RAFV600E. However, PLX4032 displays limited effect in colon cancer patients that also carrying B-RAFV600E oncoprotein. The reason for this is that, in colon cancer cells, B-RAFV600E inhibition by PLX4032 results in a rapid feedback EGFR activation, which compensates for the PLX4032-inhibited cell proliferation. [3]
In vivo In B-RAFV600E-mutant mice xenograft models, PLX4032 (6 mg/kg–20 mg/kg) inhibits tumor growth. [1] In mice xenograft models of LOX, Colo829, and A375 cells, PLX4032 (12.5 mg/kg–100 mg/kg) inhibits tumor growth and prolongs mice survival. [2]
Features A novel and potent inhibitor of the B-RAFV600E oncoprotein.

Protocol(Only for Reference)

Kinase Assay: [1]

RAF kinase activity measurements The kinase activities of wild-type RAF and mutants are determined by measuring phosphorylation of biotinylated-BAD protein. For each enzyme (0.01 ng), 20 μL reactions are carried out in 20 mM Hepes (pH 7.0), 10 mM MgCl2, 1 mM DTT, 0.01% (v/v) Tween-20, 50 nM biotin-BAD protein, and 1 mM ATP at room temperature. Reactions are stopped at 5 min with 5 μL of a solution containing 20 mM Hepes (pH 7.0), 200 mM NaCl, 80 mM EDTA, 0.3% (w/v) bovine serum albumin (BSA). The stop solution also includes phospho-BAD (Ser112) antibody, streptavidin-coated donor beads, and protein A acceptor beads. The antibody and beads are pre-incubated in stop solution in the dark at room temperature for 30 min. The final dilution of antibody is 1/2000 and the final concentration of each bead is 10 μg/mL. The assay plates are incubated at room temperature for one hour and then are read on a PerkinElmer AlphaQuest reader. Mutant activities are the average of two different batches of purified protein assayed in duplicate in three different experiments.

Cell Assay: [2]

Cell lines MALME-3M, Colo829, Colo38, A375, SK-MEL28, and A2058 cells
Concentrations 0–10 μM , dissolved in DMSO
Incubation Time 5 days
Method Cellular proliferation is evaluated by MTT assay. Briefly, cells are plated in 96-well microtiter plates at a density of 1000 to 5000 cells per well in a volume of 180 μL. PLX4032 is prepared at 10 times the final assay concentration in media containing 1% DMSO. Twenty-four hours after cell plating, 20 μL of the appropriate dilution of PLX4032 are added to plates in duplicate. The plates are assayed for proliferation 6 days after the cells are plated. Percent inhibition is calculated and the IC50 is determined from the regression of a plot of the logarithm of the concentration versus percent inhibition.

Animal Study: [2]

Animal Models Mice (athymic nude) xenograft models of LOX, Colo829, and A375 cells
Formulation Formulated as microprecipitated bulk powder (MBP), suspended at the desired concentration in an aqueous vehicle containing 2% Klucel LF, and adjusted to pH 4 with dilute HCl
Dosages 12.5 mg/kg–100 mg/kg
Administration Oral gavage twice daily
Solubility 30% PEG400/0.5% Tween80/5% propylene glycol, , 5 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.

Conversion of different model animals based on BSA (Value based on data from FDA Draft Guidelines)

SpeciesBaboonDogMonkeyRabbitGuinea pigRatHamsterMouse
Weight (kg)121031.80.40.150.080.02
Body Surface Area (m2)0.60.50.240.150.050.0250.020.007
Km factor202012128653
Animal A (mg/kg) = Animal B (mg/kg) multiplied by  Animal B Km
Animal A Km

For example, to modify the dose of resveratrol used for a mouse (22.4 mg/kg) to a dose based on the BSA for a rat, multiply 22.4 mg/kg by the Km factor for a mouse and then divide by the Km factor for a rat. This calculation results in a rat equivalent dose for resveratrol of 11.2 mg/kg.

Rat dose (mg/kg) = mouse dose (22.4 mg/kg) ×  mouse Km(3)  = 11.2 mg/kg
rat Km(6)
1

References

[1] Bollag G, et al. Nature, 2010, 467(7315), 596-599.

[2] Yang H, et al. Cancer Res, 2010, 70(13), 5518-5527.

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Clinical Trial Information( data from http://clinicaltrials.gov, updated on 2014-09-20)

NCT Number Recruitment Conditions Sponsor
/Collaborators
Start Date Phases
NCT02230306 Not yet recruiting Active Melanoma Brain Metastases Hussein Tawbi|Genentech|University of Pittsburgh August 2014 Phase 2
NCT02042040 Not yet recruiting Melanoma University of Utah August 2014 Phase 1
NCT02164916 Not yet recruiting Colorectal Cancer Southwest Oncology Group|National Cancer Institute (NCI)|Genentech/Roche July 2014 Phase 2
NCT02145910 Not yet recruiting Recurrent Melanoma|Stage IV Melanoma|Tumors Metastatic to Brain Thomas Jefferson University|Genentech June 2014 Phase 1
NCT02145143 Recruiting Thyroid Carcinoma Memorial Sloan-Kettering Cancer Center|Genentech May 2014 --

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Chemical Information

Download Vemurafenib (PLX4032, RG7204) SDF
Molecular Weight (MW) 489.92
Formula

C23H18ClF2N3O3S

CAS No. 918504-65-1
Storage 3 years -20℃Powder
6 months-80℃in DMSO
Synonyms RO5185426
Solubility (25°C) * In vitro DMSO 98 mg/mL (200 mM)
Water <1 mg/mL (<1 mM)
Ethanol <1 mg/mL (<1 mM)
In vivo 30% PEG400/0.5% Tween80/5% propylene glycol, 5 mg/mL
* <1 mg/ml means slightly soluble or insoluble.
* 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.

Research Area

Customer Reviews (9)


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Rating
Source Nature 2012 483(7387):100-3. Vemurafenib (PLX4032, RG7204) purchased from Selleck
Method Colony formation assay
Cell Lines Thyroid cancer (8505C)/CRC (OXCO-1, COLO741 and WiDr)/melanoma (A375) cells
Concentrations 0/0.15/0.31/0.63/1/25 uM
Incubation Time 10-14 days
Results Of the ten colorectal cancer cell lines examined, eight express much higher levels of EGFR, but in two (COLO-741 and OXCO-1) EGFR levels were as low as those seen in melanoma. All three thyroid cancer cell lines expressed EGFR at significant levels. When we tested the two EGFRlow CRC cell lines for their response to PLX4032, we found them to be almost as sensitive as the melanoma cell line A375 in both short-term assays and long-term assays.

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Rating
Source Nature 2012 483(7387):100-3. Vemurafenib (PLX4032, RG7204) purchased from Selleck
Method Western blot
Cell Lines PC9GR4/WZR10 cells
Concentrations 1 uM
Incubation Time 72 h
Results Co-treatment of these cells with a combination of PLX4032 and either cetuximab or gefitinib prevented this feedback activation of EGFR. PLX4032 treatment inhibited MEK and ERK activation downstream of BRAF but activated AKT, which acts downstream of EGFR in a pathway parallel to BRAF. We note that in all three cell lines treatment with BRAF and EGFR inhibitors caused a more complete inhibition of AKT, MEK and ERK signalling as compared to PLX4032 monotherapy, providing a rationale for the observed synergy in growth assays.

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Rating
Source J Invest Dermatol 2013 133, 2041. Vemurafenib (PLX4032, RG7204) purchased from Selleck
Method Western blot
Cell Lines A375 melanoma cells
Concentrations 0-10 μM
Incubation Time 6 h
Results The activation of Stat3 and the protein expression of PAX3 were both repressed in vemurafenib-sensitive (parental) A375 and UACC62 melanoma cells, but higher vemurafenib concentration were required in resistant A375 and UACC62 melanoma cells. Specifically, vemurafenib at 1 μM inhibited the expression of phospho-Stat3 in sensitive cells, but not in resistant cells. These results suggest that inhibition of Stat3 signaling represents a potential therapeutic strategy to overcome the acquired resistance to vemurafenib in melanoma cells.

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Rating
Source J Invest Dermatol 2011 131, 2087-95. Vemurafenib (PLX4032, RG7204) purchased from Selleck
Method Clonogenic assays
Cell Lines VM21/VM1 (c) cells
Concentrations 0.1 μM
Incubation Time 14 d
Results Combination of PD166866 with the V600E BRAF-specific inhibitor RG7204 (PLX4032) potently reduced clonogenic growth of VM21 and VM1 cells.

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Rating
Source Oncoimmunology 2012 1, 1476-1483. Vemurafenib (PLX4032, RG7204) purchased from Selleck
Method flow cytometry
Cell Lines tumor-infiltrating lymphocytes
Concentrations 100-250 nM
Incubation Time 72 h
Results Treatment with Vem significantly increased the frequency of TILs recognizing autologous melanoma cells and responding to them by producing Type 1 helper cytokines (Fig. A ) or by mobilizing cytotoxic granules (Fig. B ), confirming the polyfunctionality of newly-induced responses.

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Rating
Source Dr. Zhe-Sheng Chen of St. John's University. Vemurafenib (PLX4032, RG7204) purchased from Selleck
Method Cell cytotoxicity assay
Cell Lines HEK293 cells, HEK293/MRP7 cells
Concentrations 20 μM
Incubation Time
Results

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Rating
Source Dr. Zhe-Sheng Chen of St. John's University. Vemurafenib (PLX4032, RG7204) purchased from Selleck
Method Cell cytotoxicity assay
Cell Lines H460 cells, H460/MX20 cells
Concentrations 20 μM
Incubation Time
Results

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Rating
Source Dr. Zhe-Sheng Chen of St. John's University. Vemurafenib (PLX4032, RG7204) purchased from Selleck
Method [3H]-Mitoxantrone accumulation analysis
Cell Lines H460 cells, H460/MX20 cells
Concentrations 20 μM
Incubation Time 96 h
Results Vemurafenib increased the intra-cellular accumulation of Mitoxantrone in ABCG2 overexpressing H460/MX20 cells compared with parental H460 cells.

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Rating
Source Vemurafenib (PLX4032, RG7204) purchased from Selleck
Method Western blot analysis/ In vitro colony formation assay
Cell Lines LOX IMVI melanoma cells
Concentrations 0-1 μM
Incubation Time 24 h
Results We therefore a ssessed the effe ct of the anti-E rbB3 anti-body A4 generated in our lab and able to inhibit the ligand-induced signaling and to potently induce receptor internalization and degradation, on vemurafenib-induced pErbB3 and pAKT levels and found that this was able to completely abrogate receptor phosphory l-ation and AKT signaling in all cell line s tested (Figure a)treatment with anti-ErbB3 mAb strongly potentiated growth inhibition by vemurafenib (Figure b and c). As expected only A3 but not A2 was able to completely abrogate vemurafenib-induced ErbB3 phosphorylation and AKT signaling (Figure d). Moreover in in vitro colony formation a ssays only A3 but not A2 strongly potentiated growth inhibition by vemurafenib(Figure e).

Product Citations (46)

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