PLX8394 is an orally active BRAF small molecule inhibitor with IC50 of 3.8 nM for BRAF(V600E), 14 nM for WT BRAF and 23 nM for CRAF. It has potential antitumor activity[1]. PLX8394 is a potent inhibition of ERK1/2 phosphorylation in cells at concentrations above 25 nM, and in parental cells at a lower threshold of 10 nM. This compound effectively diminishes levels of cyclin D3 and cyclin D1, phosphorylation of retinoblastoma protein, and expression of cyclin A2 in both parental and PRT cells. Additionally, PLX8394 is capable of inhibiting ERK1/2 phosphorylation and growth in PLX4032-resistant cells that possess a BRAF V600K/L505H double mutation or a transposon-induced, N-terminal truncated form of BRAF[1]. PLX8394 also significantly reduces tumor cell growth and curtails MAPK signaling in LA cell lines harboring either the endogenous V600E mutation or non-V600 mutant forms of BRAF[2].
体内研究
When administered at a dose of 150 mg/kg/day, PLX8394 substantially reduces tumor growth and MAPK pathway signaling, as well as tumor cell proliferation in H1755 xenograft tumors, demonstrating its efficacy without causing overt toxicity in mice. The combination of PLX8394 with CP-358774 results in plasma concentrations of CP-358774 exceeding 1 μM[2].
体外研究
PLX8394 is an orally active BRAF small molecule inhibitor with IC50 of 3.8 nM for BRAF(V600E), 14 nM for WT BRAF and 23 nM for CRAF. It has potential antitumor activity[1].
PLX8394 is a potent inhibition of ERK1/2 phosphorylation in cells at concentrations above 25 nM, and in parental cells at a lower threshold of 10 nM. This compound effectively diminishes levels of cyclin D3 and cyclin D1, phosphorylation of retinoblastoma protein, and expression of cyclin A2 in both parental and PRT cells. Additionally, PLX8394 is capable of inhibiting ERK1/2 phosphorylation and growth in PLX4032-resistant cells that possess a BRAF V600K/L505H double mutation or a transposon-induced, N-terminal truncated form of BRAF[1].
PLX8394 also significantly reduces tumor cell growth and curtails MAPK signaling in LA cell lines harboring either the endogenous V600E mutation or non-V600 mutant forms of BRAF[2].
PLX8394 细胞实验
Cell Line
Concentration
Treated Time
Description
References
LIM2405 cells
1 µM
6 hours
Both PLX8394 and vemurafenib reduced pMEK and pERK levels
Mol Cancer. 2017 Jun 28;16(1):112.
COLO 201 cells
1 µM
6 hours
Both PLX8394 and vemurafenib reduced pMEK and pERK levels
Mol Cancer. 2017 Jun 28;16(1):112.
SK-MEL-239 cells
39 nM
1 hour
PLX8394 inhibited p-ERK in SK-MEL-239 cells with an IC75 of 39 nM
Nat Med. 2019 Feb;25(2):284-291.
SK-MEL-239 C4 cells
158 nM
1 hour
PLX8394 inhibited p-ERK in SK-MEL-239 C4 cells with an IC75 of 158 nM
Nat Med. 2019 Feb;25(2):284-291.
293H (NRAS Q61K) cells
100–300 nM
1 hour
PLX8394 significantly reduced the levels of RAS-dependent full-length BRAF/BRAF or BRAF/CRAF dimers and RAS-independent BRAF dimers (p61 BRAF) in 293H (NRAS Q61K) cells with an IC50 of 100–300 nM
Nat Med. 2019 Feb;25(2):284-291.
HEK293 cells
1 µM
15 minutes
Assess the impact of PLX8394 on BRAF-V600E KinCon reporter dynamics, showing that PLX8394 exposure promotes an immediate closing event.
Proc Natl Acad Sci U S A. 2020 Dec 8;117(49):31105-31113.
Human Dermal Fibroblasts (HDF)
2 µM
18 hours
To evaluate the effect of PLX8394 on the proliferative state of HDF, results showed that PLX8394 did not increase cell proliferation
Cell Commun Signal. 2021 Dec 20;19(1):123.
RT3 cells
10 µM
24 hours
PLX8394 significantly inhibited TGF-β signaling, reduced phosphorylation of Smad2 and TGF-β receptor II, as well as p38 activity, MMP-1 and MMP-13 synthesis, and decreased laminin-332 accumulation.
Oncogene. 2023 Dec;42(49):3633-3647.
HaCaT cells
10 µM
24 hours
PLX8394 completely prevented TGF-β-induced Smad2 phosphorylation in both HaCaT and RT3 cells.
Oncogene. 2023 Dec;42(49):3633-3647.
HEK293T cells
1 µM
4 hours
PLX8394 failed to induce BRAF/RAF1 heterodimers, indicating its inhibitory effect on RAF dimerization
Cell Commun Signal. 2023 Jun 14;21(1):136.
A2058 melanoma cells
10 µM
4 hours and 18 hours
PLX8394 blocked Smad2 activation in A2058 melanoma cells.
Oncogene. 2023 Dec;42(49):3633-3647.
LM-COL-1 cells
1 µM
6 hours
PLX8394 had minimal effect on pMEK and pERK, while vemurafenib caused a significant increase in pMEK and pERK
Mol Cancer. 2017 Jun 28;16(1):112.
ALA cells
1 µM
6 hours
PLX8394 had minimal effect on pMEK and pERK, while vemurafenib caused a significant increase in pMEK and pERK
Mol Cancer. 2017 Jun 28;16(1):112.
LS513 cells
1 µM
6 hours
PLX8394 had minimal effect on pMEK and pERK, while vemurafenib caused a significant increase in pMEK and pERK
Mol Cancer. 2017 Jun 28;16(1):112.
HCT 116 cells
1 µM
6 hours
PLX8394 had minimal effect on pMEK and pERK, while vemurafenib caused a significant increase in pMEK and pERK
Mol Cancer. 2017 Jun 28;16(1):112.
HEK293 cells
1 nM
Assess the impact of PLX8394 on BRAF-N581S KinCon reporter dynamics, showing an immediate closing effect with the lowest dose of PLX8394.
Proc Natl Acad Sci U S A. 2020 Dec 8;117(49):31105-31113.
LM-COL-1
1 μM
6 h
To verify whether CCcould avoid paradoxical activation of the MAPK signaling pathway in LM-COL-1 cells, results showed minimal effect of PLX8394 on pMEK and pERK.
Mol Cancer. 2017 Jun 28;16(1):112.
ALA
1 μM
6 h
To verify whether PLX8394 could avoid paradoxical activation of the MAPK signaling pathway in ALA cells, results showed minimal effect of PLX8394 on pMEK and pERK.
Mol Cancer. 2017 Jun 28;16(1):112.
LS513
1 μM
6 h
To verify whether PLX8394 could avoid paradoxical activation of the MAPK signaling pathway in LS513 cells, results showed minimal effect of PLX8394 on pMEK and pERK.
Mol Cancer. 2017 Jun 28;16(1):112.
HCT 116
1 μM
6 h
To verify whether PLX8394 could avoid paradoxical activation of the MAPK signaling pathway in HCT 116 cells, results showed minimal effect of PLX8394 on pMEK and pERK.
Mol Cancer. 2017 Jun 28;16(1):112.
PLX8394 动物实验
Species
Animal Model
Administration
Dosage
Frequency
Description
References
SCID/SCID mice
Human cSCC xenograft model
Oral
150 mg/kg
Once daily for 18 days
PLX8394 significantly suppressed the growth of human cSCC xenograft tumors and reduced collagen degradation in the tumors.
Oncogene. 2023 Dec;42(49):3633-3647.
SCID/SCID mice
Human cSCC xenograft model
Oral gavage
150 mg/kg
Once daily for 18 days
Significantly inhibits the growth of human cSCC tumors and reduces in vivo collagen degradation
Oncogene. 2023 Dec;42(49):3633-3647.
SCID/SCID mice
CSCC xenograft model
Oral
150 mg/kg
Once daily for 18 days
PLX8394 significantly suppressed the growth of cSCC xenograft tumors and reduced collagen degradation in tumors, indicating its therapeutic potential for cSCC.
Oncogene. 2023 Dec;42(49):3633-3647.
NOD/SCID mice
Fibroblastoma model
Oral
200 mg/kg
Twice a day until the experimental endpoint
To evaluate the inhibitory effect of PLX8394 on fibroblastomas induced by BRAF mutants, results showed that PLX8394 significantly inhibited tumor growth
Theranostics. 2025 Jan 6;15(5):2035-2051
Nude mice
Melanoma xenograft model
Oral
50 mg/kg
Twice daily, continuous treatment
PLX8394 was well tolerated in melanoma xenograft models and effectively inhibited tumor growth at a dose of 50 mg/kg
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