The RAS/RAF signaling pathway is an important mediator of tumor cell proliferation and angiogenesis. PLX4720 is a potent and selective inhibitor of B-RafV600E mutant, with less potent to wt-braf and BRK with IC50 values of 160nM and 130nM, and showed selectivity to B-RafV600E mutant over 100 fold against a diverse panel of 70 other kinases. Consistent with the in vitro study, PLX4720 showed more potent anti-proliferation in tumor cell lines bearing the B-RafV600E oncogene with GI50<1.7μM,such as COLO205, A375, WM2664 and COLO829 cells, versus GI50>10μM on cells with wt-braf. PLX4720 initiates antimelanoma activity, inhibition of MAPK pathway represented suppressed p-ERK, apoptotic response only in cells harboring the V600E mutation. Daily oral gavage of PLX4720, at dose of 20mg/kg 14 days resulted in substantial block of tumor growth and a 21-day tumor growth delay, with ERK phosphorylation inhibited by 43% in treated tumors, in COLO205 xenograft model[1].
作用机制
PLX4720 is an ATP competitive kinase inhibitor.[1]
PLX4720 细胞实验
Cell Line
Concentration
Treated Time
Description
References
A375
0.66 μM
24 h
Generate sub-lines with acquired resistance to PLX4720
Nat Commun. 2019 Nov 14;10(1):5167.
NAE cells
1 µM, 3 µM, 10 µM, 30 µM
48 h
To evaluate the synergistic effect of PLX4720 with Nt-3, results showed significant synergism in NAE cells
Clin Cancer Res. 2013 Aug 15;19(16):4383-91.
A375 cells
2 µM
24 h
To evaluate the effect of PLX4720 on A375 cells, results showed decreased levels of pERK and cyclinD1
Clin Cancer Res. 2013 Aug 15;19(16):4383-91.
WM239 cells
2 µM
24 h
To evaluate the effect of PLX4720 on WM239 cells, results showed decreased levels of pERK and cyclinD1
Clin Cancer Res. 2013 Aug 15;19(16):4383-91.
LM-MEL-33, LM-MEL-64, LM-MEL-70
1 μM
0, 3, 7, 11, 17, 35, and 70 days
To evaluate the effect of PLX4720 on melanoma cell lines harboring BRAF activating mutations and observe phenotypic changes post-treatment. Results showed significant phenotypic changes after 3 days of drug treatment, followed by stabilization at 11, 17, and 35 days. Chronic exposure to PLX4720 resulted in similar cell phenotypes, indicating the selection effect of drug resistance.
Nat Commun. 2018 Apr 16;9(1):1482.
A375 cells
5 µM
8-72 h
To test the protective effect of TNF α on PLX4720-induced apoptosis, results showed that TNF α significantly inhibited the activation of caspase 3, 8, and 9 induced by PLX4720.
J Invest Dermatol. 2015 Jul;135(7):1839-1848.
M238 cells
5 µM
8-72 h
To test the protective effect of TNF α on PLX4720-induced apoptosis, results showed that TNF α significantly inhibited the activation of caspase 3, 8, and 9 induced by PLX4720.
J Invest Dermatol. 2015 Jul;135(7):1839-1848.
M229 cells
5 µM
8-72 h
To test the protective effect of TNF α on PLX4720-induced apoptosis, results showed that TNF α significantly inhibited the activation of caspase 3, 8, and 9 induced by PLX4720.
J Invest Dermatol. 2015 Jul;135(7):1839-1848.
PLX4720 动物实验
Species
Animal Model
Administration
Dosage
Frequency
Description
References
Mice
Apc Min +/− mice
Oral
60 mg/kg
Daily for 28 days
To evaluate the effect of PLX4720 on intestinal polyp formation in Apc Min +/? mice, the results showed that PLX4720 significantly increased the number of intestinal polyps in mice.
Clin Cancer Res. 2015 Dec 1;21(23):5215-21
Mice
BrafV600E-mutant melanoma model
Oral
417mg/kg
4 days
PLX4720 was used to inhibit BRAF mutation, delaying tumor growth, but alone it failed to prevent tumor relapse.
Immunity. 2016 Apr 19;44(4):924-38
Mice
Braf/Nf1 mutant melanoma allograft model
Intraperitoneal injection
2.5mg/kg
Daily for 7 days
To evaluate the therapeutic effect of PLX4720 on Braf/Nf1 mutant melanomas, results showed these tumors were relatively insensitive to PLX4720
Cancer Discov. 2013 Mar;3(3):338-49
Nude mice
A375 xenograft model
Intraperitoneal injection
50 mg/kg
Once daily for two weeks
To evaluate the inhibitory effect of PLX4720 on tumor growth, results showed PLX4720 significantly suppressed tumor growth
Clin Cancer Res. 2013 Aug 15;19(16):4383-91.
Nude mice
WM35 and WM983B xenograft model
Oral
417 mg/kg
Once daily for 21 days
To study the effect of ROR1 knockdown on the response to PLX4720 treatment, results showed that ROR1 knockdown significantly decreased sensitivity to PLX4720
Cancer Discov. 2013 Dec;3(12):1378-93
Nude mice
A375TR xenograft model
Oral
90 mg/kg
Once daily for 28 days
To test the anti-tumor effect of PLX4720 combined with NFκB pathway inhibitors, results showed that combination therapy significantly inhibited tumor growth.
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