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PLX-4720 Chemical Structure
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Biological Activity
PLX4720, a 7-azaindole derivative that inhibits B-RafV600E with an IC50 of 13 nM, defines a class of kinase inhibitor with marked selectivity in both biochemical and cellular assays. PLX4720 preferentially inhibits the active B-RafV600E kinase compared with a broad spectrum of other kinases (IC50:B-Raf=160 nM, BRK=130 nM, other kinases >1000nM), and potent cytotoxic effects are also exclusive to cells bearing the V600E allele (GI50<1.7 μM, while other wild cell GI50>10μM). [1]
Consistent with the high degree of selectivity, ERK phosphorylation is potently inhibited by PLX4720 in B-RafV600E -bearing tumor cell lines but not in cells lacking oncogenic B-Raf. [1]
In B-RafV600E -dependent tumor xenograft models, orally dosed PLX4720 causes significant tumor growth delays, including tumor regressions, without evidence of toxicity. [1]
References on PLX-4720
- [1] PNAS December 1, 2009;106:20411–20416
Chemical Information
| Molecular Weight (WM): | 413.83 |
|---|---|
| Formula: | C17H14ClF2N3O3S |
| CAS No.: | 918505-84-7 |
| Synonyms: |
N/A
|
| Dissolve in (25°C): | DMSO ≥83mg/mL |
| Water <1mg/mL | |
| Ethanol <1mg/mL | |
| Storage: | 2 years-20°CPowder |
| 1 week-4°Cin DMSO | |
| 1 month-80°in DMSO |
Quality Control & MSDS
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Selleck's high quality products have been used in several published research findings, including the following:
Differential inhibitor sensitivity between human kinases VRK1 and VRK2.
BRAF Gene Amplification Can Promote Acquired Resistance to MEK Inhibitors in Cancer Cells Harboring the BRAF V600E Mutation
Mutation that blocks ATP binding creates a pseudokinase stabilizing the scaffolding function of kinase suppressor of Ras, CRAF and BRAF.
PTEN Loss Confers BRAF Inhibitor Resistance to Melanoma Cells through the Suppression of BIM Expression.
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B-RafV600E mutated melanoma line, SK-MEL-28, was treated with different doses of PLX-4720 for 4 h or 22 h. Cell lysates were analyzed by Western blotting to determine the levels of phosphorylated MEK1/2 (pMEK1/2) and phosphorylated ERK1/2 (pERK1/2). MEK1/2 is the substrate of B-Raf while ERK1/2 is the substrate of MEK1/2. Data show that phosphorylation of MEK1/2 and ERK1/2 was significantly inhibited by PLX-4720 treatment although total MEK1/2 or ERK1/2 protein levels were not affected. No pMEK1/2 or pERK1/2 signal was detected even after prolonged exposure, indicating that the inhibitor at 1 μM is very effective in blocking the constitutive kinase activity of B-RafV600E. This data is consistent with the previous result demonstrating the effect of PLX-4720 in the B-RafV600E mutated melanoma line, A375 – Fig. 2A, Nature 464:431 (2010)
B-RafV600E mutated melanoma line, SK-MEL-28, was treated with different doses of PLX-4720 for 4 h or 22 h. Cell lysates were analyzed by Western blotting to determine the levels of phosphorylated MEK1/2 (pMEK1/2) and phosphorylated ERK1/2 (pERK1/2). MEK1/2 is the substrate of B-Raf while ERK1/2 is the substrate of MEK1/2. Data show that phosphorylation of MEK1/2 and ERK1/2 was significantly inhibited by PLX-4720 treatment although total MEK1/2 or ERK1/2 protein levels were not affected. No pMEK1/2 or pERK1/2 signal was detected even after prolonged exposure, indicating that the inhibitor at 1 μM is very effective in blocking the constitutive kinase activity of B-RafV600E. This data is consistent with the previous result demonstrating the effect of PLX-4720 in the B-RafV600E mutated melanoma line, A375 – Fig. 2A, Nature 464:431 (2010)
Data independently produced by Dr Jong-In Park of Medical College of Wisconsin PLX-4720 purchased from Selleck
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A dose titration of PLX-4720 in A375 melanoma cells which possess a V600E B-Raf mutation.Effects of increasing PLX-4720 dose on Erk phosphorylation and on tumor cell proliferation as determined by MTT assay are shown.
A dose titration of PLX-4720 in A375 melanoma cells which possess a V600E B-Raf mutation.Effects of increasing PLX-4720 dose on Erk phosphorylation and on tumor cell proliferation as determined by MTT assay are shown.
Data independently produced by Dr Daniel C.Cho of Harvard Medical School PLX-4720 purchased from Selleck
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RAF inhibitors induce dimer formation between KSR and RAF, and activate KSR by CRAF. (A) GDC0879 but not PLX4720 induces BRAF/CRAF dimers. Cells overexpressing myc-CRAF and BRAF were treated with drug for 1 h and CRAF immunoprecipitates were immunoblotted for BRAF and CRAF (epitope tagged with myc). (B) GDC0879 but not PLX4720 enhances KSR/BRAF complexes. KSR immunoprecipitates were prepared from cells overexpressing FLAG-KSR and BRAF after treatment with the indicated drug for 1 h and immunoblotted using antibodies to BRAF. (C) Both GDC0879 and PLX4720 induce KSR/CRAF complexes.KSR immunoprecipitates were prepared from cells overexpressing FLAG-KSR and myc-CRAF after treatment with the indicated drug for 1 h and immunoblotted for CRAF using myc antibodies. (D and E) Requirement of KSR for drug-induced ERK activation. Lysates fromwild-type and KSR deficient fibroblasts, transfected with RASV12, were treated with the indicated doses of either GDC-0879 (D) or PLX4720 (E) for 1 h. Lysates were immunoblotted for phospho-ERK1 and 2, ERK2, and RASV12. (F) KSR and CRAF cooperate to activate MEK. Cells expressing the indicated constructs were treated with a 50 uM PLX4720 for 2 h before cell lysates were prepared and analyzed for pMEK by immunoblotting. CRAF(TM) refers to the T421M gatekeeper mutant that cannot bind to the drug(4). (G) KSR in vitro kinase reactions. Cells were cotransfected with WT or ATP binding deficient KSR and CRAF and immunoprecipitates prepared after cells were treated with an activating dose of PLX (10 uM) for 1 h. KSR immunoprecipitates were prepared, pretreated with 50 uM PLX4720 to inhibit coprecipitating RAF activity, and then tested for kinase activity using purified MEK. MEK phosphorylation was detected using a pMEK specific antibody. - RAF inhibitors induce dimer formation between KSR and RAF, and activate KSR by CRAF. (A) GDC0879 but not PLX4720 induces BRAF/CRAF dimers. Cells overexpressing myc-CRAF and BRAF were treated with drug for 1 h and CRAF immunoprecipitates were immunoblotted for BRAF and CRAF (epitope tagged with myc). (B) GDC0879 but not PLX4720 enhances KSR/BRAF complexes. KSR immunoprecipitates were prepared from cells overexpressing FLAG-KSR and BRAF after treatment with the indicated drug for 1 h and immunoblotted using antibodies to BRAF. (C) Both GDC0879 and PLX4720 induce KSR/CRAF complexes.KSR immunoprecipitates were prepared from cells overexpressing FLAG-KSR and myc-CRAF after treatment with the indicated drug for 1 h and immunoblotted for CRAF using myc antibodies. (D and E) Requirement of KSR for drug-induced ERK activation. Lysates fromwild-type and KSR deficient fibroblasts, transfected with RASV12, were treated with the indicated doses of either GDC-0879 (D) or PLX4720 (E) for 1 h. Lysates were immunoblotted for phospho-ERK1 and 2, ERK2, and RASV12. (F) KSR and CRAF cooperate to activate MEK. Cells expressing the indicated constructs were treated with a 50 uM PLX4720 for 2 h before cell lysates were prepared and analyzed for pMEK by immunoblotting. CRAF(TM) refers to the T421M gatekeeper mutant that cannot bind to the drug(4). (G) KSR in vitro kinase reactions. Cells were cotransfected with WT or ATP binding deficient KSR and CRAF and immunoprecipitates prepared after cells were treated with an activating dose of PLX (10 uM) for 1 h. KSR immunoprecipitates were prepared, pretreated with 50 uM PLX4720 to inhibit coprecipitating RAF activity, and then tested for kinase activity using purified MEK. MEK phosphorylation was detected using a pMEK specific antibody.
Data from [Proc Natl Acad Sci USA 2011.January;108:6067-6072] PLX-4720 purchased from Selleck
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PTEN predicts for PLX4720-induced apoptosis. A, basal PTEN and phospho-AKT(pAKT; S473, T308) expression in PTENt (WM164, 451Lu, SK-mel-28, WM983A, WM35, WM51) and PTEN (WM239A, WM266-4, WM793, M233, WM9, 1205Lu) melanoma cell lines. B, MTT assay of PTENt (gray)-expressing versus PTEN (black) cell lines. C, PTENt cells are more sensitive than PTEN cells to PLX4720-mediated apoptosis. Cells treated for 48 hours with 3 or 10 mmol/L PLX4720 before being stained for TMRM and Annexin-V. Apoptosis was measured by flow cytometry. Data shows mean SE mean of 3 independent experiments.*, PTENt cohort significantly different from PTEN cohort(P < 0.05). - PTEN predicts for PLX4720-induced apoptosis. A, basal PTEN and phospho-AKT(pAKT; S473, T308) expression in PTENt (WM164, 451Lu, SK-mel-28, WM983A, WM35, WM51) and PTEN (WM239A, WM266-4, WM793, M233, WM9, 1205Lu) melanoma cell lines. B, MTT assay of PTENt (gray)-expressing versus PTEN (black) cell lines. C, PTENt cells are more sensitive than PTEN cells to PLX4720-mediated apoptosis. Cells treated for 48 hours with 3 or 10 mmol/L PLX4720 before being stained for TMRM and Annexin-V. Apoptosis was measured by flow cytometry. Data shows mean SE mean of 3 independent experiments.*, PTENt cohort significantly different from PTEN cohort(P < 0.05).
Data from [Cancer Res 2011.February;71:2750-2760] PLX-4720 purchased from Selleck
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Loss of PTEN is associated with PI3K/AKT signaling following BRAF inhibition. A, PTENt (WM35, WM164, WM983A) and PTEN (M233, WM9,WM793, 1205Lu) cells were treated with PLX4720 (24 hours: 0.03–3 mmol/L) and probed for phospho-PDK1 (pPDK1), total PDK1, phospho-AKT (pAKT), total AKT (tAKT), phospho-S6 (pS6), and total S6. Numbers indicate relative intensity of pPDK1 normalized to PDK1 and pAKT normalized to tAKT. B, PLX4720 increases pAKT following PTEN knockdown. WM35 cells were incubated with nontargeting siRNA (NT) or 2 different PTEN-specific siRNA's (PTEN) before treatment with either vehicle or PLX4720 (3 mmol/L). C, siRNA knockdown of BRAF increases pAKT in melanoma cell lines that are PTEN. WM164 (PTENt) and WM793 (PTEN) cells were incubated with lipofectamine alone (L), nontargeting siRNA (NT), or BRAF-specific siRNA (BRAF). Protein was extracted, resolved, and probed for BRAF, pAKT, total AKT, and GAPDH.
Loss of PTEN is associated with PI3K/AKT signaling following BRAF inhibition. A, PTENt (WM35, WM164, WM983A) and PTEN (M233, WM9,WM793, 1205Lu) cells were treated with PLX4720 (24 hours: 0.03–3 mmol/L) and probed for phospho-PDK1 (pPDK1), total PDK1, phospho-AKT (pAKT), total AKT (tAKT), phospho-S6 (pS6), and total S6. Numbers indicate relative intensity of pPDK1 normalized to PDK1 and pAKT normalized to tAKT. B, PLX4720 increases pAKT following PTEN knockdown. WM35 cells were incubated with nontargeting siRNA (NT) or 2 different PTEN-specific siRNA's (PTEN) before treatment with either vehicle or PLX4720 (3 mmol/L). C, siRNA knockdown of BRAF increases pAKT in melanoma cell lines that are PTEN. WM164 (PTENt) and WM793 (PTEN) cells were incubated with lipofectamine alone (L), nontargeting siRNA (NT), or BRAF-specific siRNA (BRAF). Protein was extracted, resolved, and probed for BRAF, pAKT, total AKT, and GAPDH.
Data from [Cancer Res 2011.February;71:2750-2760] PLX-4720 purchased from Selleck
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Dual PI3K/BRAF inhibition upregulates BIM and enhances apoptosis in PTEN cells. A, left, Western blot of 1205Lu cells treated with PLX4720 (3 mmol/L, 48 hours), the PI3K inhibitor GDC-0941 (3 mmol/L, 48 hours), or both drugs in combination (PtG); right, immunofluorescence staining of BIM (green) and DAPI (blue) in PTEN cells following PLX4720 treatment (3mmol/L, 48 hours), the PI3K inhibitor LY294002 (10 mmol/L, 48 hours), or both drugs in combination (PLXtLY). B, left, immunofluorescence staining of PTEN 1205Lu following combined inhibition (3 mmol/L PLX4720 t 10 mmol/L LY294002, 48hours) increases nuclear localization of FOXO3a (green). DAPI is shown in blue. Magnification 40. Right, combined inhibition (3 mmol/L PLX4720 t 10 mmol/L LY294002, 48 hours) increases PTEN WM793 BIM mRNA levels to those observed with single BRAF inhibition (3 mmol/L PLX4720, 48 hours) in the PTENt WM35. C, PTEN cells were treated with PLX4720 (3 mmol/L, 48 hours), GDC-0941 (3 mmol/L, 48hours), or a combination of the 2 drugs (3Pt3G) before Annexin-V staining was analyzed by flow cytometry (*, P < 0.05 between the drug combination and each inhibitor alone). D, combined BRAF/PI3K inhibitor treatment blocks the escape of 1205Lu cells (PTEN) from therapy. Spheroids of 1205Lu cells were treated with either PLX4720 alone (3 and 10 mmol/L: data shows 3 mmol/L), LY294002 (10 mmol/L) alone or a combination of the 2 drugs for 72 hours. In other studies, spheroids were treated with drugs for 72 hours and then allowed to recover for 120 hours. Micrograph shows viability staining (green ?live cells, red ?dead cells). Magnification 10. - Dual PI3K/BRAF inhibition upregulates BIM and enhances apoptosis in PTEN cells. A, left, Western blot of 1205Lu cells treated with PLX4720 (3 mmol/L, 48 hours), the PI3K inhibitor GDC-0941 (3 mmol/L, 48 hours), or both drugs in combination (PtG); right, immunofluorescence staining of BIM (green) and DAPI (blue) in PTEN cells following PLX4720 treatment (3mmol/L, 48 hours), the PI3K inhibitor LY294002 (10 mmol/L, 48 hours), or both drugs in combination (PLXtLY). B, left, immunofluorescence staining of PTEN 1205Lu following combined inhibition (3 mmol/L PLX4720 t 10 mmol/L LY294002, 48hours) increases nuclear localization of FOXO3a (green). DAPI is shown in blue. Magnification 40. Right, combined inhibition (3 mmol/L PLX4720 t 10 mmol/L LY294002, 48 hours) increases PTEN WM793 BIM mRNA levels to those observed with single BRAF inhibition (3 mmol/L PLX4720, 48 hours) in the PTENt WM35. C, PTEN cells were treated with PLX4720 (3 mmol/L, 48 hours), GDC-0941 (3 mmol/L, 48hours), or a combination of the 2 drugs (3Pt3G) before Annexin-V staining was analyzed by flow cytometry (*, P < 0.05 between the drug combination and each inhibitor alone). D, combined BRAF/PI3K inhibitor treatment blocks the escape of 1205Lu cells (PTEN) from therapy. Spheroids of 1205Lu cells were treated with either PLX4720 alone (3 and 10 mmol/L: data shows 3 mmol/L), LY294002 (10 mmol/L) alone or a combination of the 2 drugs for 72 hours. In other studies, spheroids were treated with drugs for 72 hours and then allowed to recover for 120 hours. Micrograph shows viability staining (green ?live cells, red ?dead cells). Magnification 10.
Data from [Cancer Res 2011.February;71:2750-2760] PLX-4720 purchased from Selleck
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LC-MRM identifies differential regulation of BIM in PTENt and PTEN cell lines following PLX4720 treatment. A, representative LC-MRM data showing the fold changes in the expression of Bak, Bax, Bcl-2, Bcl-w, Bcl-xL, BID, BIM, Bok, and Mcl-1 over internal standard in the WM164 (PTENt) and 1205Lu (PTEN) cell lines following treatment with PLX4720 (10 mmol/L, 0–48 hours). Statistical analysis of BIM fold change in PTEN versus PTENt. *, P < 0.05. B, Western blot showing BIM expression following PLX4720 treatment (10 mmol/L, 0–48 hours) in PTEN (WM793, 1205Lu) and WM164 cell lines (PTENt). C, immunofluorescence staining, showing expression of BIM and DAPI staining of PTEN (M233, WM9, WM793, 1205Lu) and PTENt (WM35, WM164, WM983A) cells following PLX4720 treatment (3 mmol/L, 48 hours).D, Western blot showing BAD phosphorylation following treatment with PLX4720 (0–48 hours) in PTEN (WM793,1205Lu) and PTENt WM164. Annexin V binding following treatment with 3 or 10 mmol/L PLX4720 (48 hours) showing increased apoptosis in WM793 stably overexpressing WT BAD. *, P < 0.05. - LC-MRM identifies differential regulation of BIM in PTENt and PTEN cell lines following PLX4720 treatment. A, representative LC-MRM data showing the fold changes in the expression of Bak, Bax, Bcl-2, Bcl-w, Bcl-xL, BID, BIM, Bok, and Mcl-1 over internal standard in the WM164 (PTENt) and 1205Lu (PTEN) cell lines following treatment with PLX4720 (10 mmol/L, 0–48 hours). Statistical analysis of BIM fold change in PTEN versus PTENt. *, P < 0.05. B, Western blot showing BIM expression following PLX4720 treatment (10 mmol/L, 0–48 hours) in PTEN (WM793, 1205Lu) and WM164 cell lines (PTENt). C, immunofluorescence staining, showing expression of BIM and DAPI staining of PTEN (M233, WM9, WM793, 1205Lu) and PTENt (WM35, WM164, WM983A) cells following PLX4720 treatment (3 mmol/L, 48 hours).D, Western blot showing BAD phosphorylation following treatment with PLX4720 (0–48 hours) in PTEN (WM793,1205Lu) and PTENt WM164. Annexin V binding following treatment with 3 or 10 mmol/L PLX4720 (48 hours) showing increased apoptosis in WM793 stably overexpressing WT BAD. *, P < 0.05.
Data from [Cancer Res 2011.February;71:2750-2760] PLX-4720 purchased from Selleck
- We have used PLX4720 in the lab and are very satisfied with its functionality.
John MariadasonLudwig Institute for Cancer ResearchAustin Hospital, Melbourne, Australia
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B-RafV600E mutated melanoma line, SK-MEL-28, was treated with different doses of PLX-4720 for 4 h or 22 h. Cell lysates were analyzed by Western blotting to determine the levels of phosphorylated MEK1/2 (pMEK1/2) and phosphorylated ERK1/2 (pERK1/2). MEK1/2 is the substrate of B-Raf while ERK1/2 is the substrate of MEK1/2. Data show that phosphorylation of MEK1/2 and ERK1/2 was significantly inhibited by PLX-4720 treatment although total MEK1/2 or ERK1/2 protein levels were not affected. No pMEK1/2 or pERK1/2 signal was detected even after prolonged exposure, indicating that the inhibitor at 1 μM is very effective in blocking the constitutive kinase activity of B-RafV600E. This data is consistent with the previous result demonstrating the effect of PLX-4720 in the B-RafV600E mutated melanoma line, A375 – Fig. 2A, Nature 464:431 (2010)
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Data independently produced by Dr Jong-In Park of Medical College of Wisconsin
A dose titration of PLX-4720 in A375 melanoma cells which possess a V600E B-Raf mutation.Effects of increasing PLX-4720 dose on Erk phosphorylation and on tumor cell proliferation as determined by MTT assay are shown.
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Data independently produced by Dr Daniel C.Cho of Harvard Medical School
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