Human epidermal growth factor receptor (EGFR; HER1,erbB1), human epidermal growth factor r eceptor 2 (HER2; erbB2), HER3 (erbB3) and HER4 (erbB4) are members of the ErbB family of transmembrane receptor tyrosine kinases. Among them, HER2 is a validated and high-value target. Approximately 30% of breast cancers have an amplification of the HER2/neu gene or overexpression of its protein product, HER2. Also, overexpression of HER2 occurs in gastric, colorectal, NSCLC and ovarian cancers. CP-724714 is a potent inhibitor of HER2 with IC50 value of 10nM (measured by kinase activity), ~640-fold selectivity for HER2 than the closely related kinase EGFR. NIH 3T3 cells transfected with chimeric EGFR/HER2 exposure to CP-724714>250nM showed decrease of EGF-induced autophosphorylation level of HER2. Colony formation was reduced by >80% by CP-724714 at concentration of 1μM in BT-474 cells and at 3μM in SKBR3 cells. Accumulation in G1 phase and a marked reduction in S-phase can be observed in BT-474 cells treated with 1μM CP-724714 for 24h. Oral administration of CP-724714 at dose ranging in 6.25-100mg/kg, q.d., resulted in dose-dependent inhibition of FRE-erbB2 xenografts and 50% tumor growth inhibition at 50mg/kg. Tumor growth inhibition by 41%, 42%, 81% and 100% achieved by 1, 10, 30, and 100 mg/kg CP-724714 in BT-474 xenografts. Also, the tumor growth inhibition of MDA-MB-453 xenografts by 19%, 66%, and 83% was achieved in the 25, 50 and 100 mg/kg b.i.d. treatment groups, respectively. Meanwhile, the reduction ranging in 69%-79% of HER2 phosphorylation in these groups treated with CP-724714 can be observed. Also, treatment with CP-724714 at 30mg/kg or 100mg/kg resulted in significant reduction of p-ERK and p-ATK, the downstreams activated by HER2, in BT-474 xenografts[1].
CP-724714 细胞实验
Cell Line
Concentration
Treated Time
Description
References
HCC1954
0.1 µM and 1 µM
To test the inhibitory effect of CP-724714 on the proliferation of HCC1954 cells. Results showed that CP-724714 alone had limited effect on cell proliferation, but when combined with the PI3K inhibitor LY294002, it significantly inhibited cell proliferation.
Int J Oncol. 2017 Oct;51(4):1320-1330
MCF10A/HER2/PIK3CA-H1047R
0.1 µM and 1 µM
9 days
To test the inhibitory effect of CP-724714 on the proliferation of MCF10A/HER2/PIK3CA-H1047R cells. Results showed that CP-724714 alone had little to no effect on cell proliferation, but when combined with the PI3K inhibitor LY294002, it significantly inhibited cell proliferation.
Int J Oncol. 2017 Oct;51(4):1320-1330
ST cells
80 μM
Evaluate the toxicity of CP-724714 on ST cells, showing no significant toxicity at concentrations below 80 μmol/L
Virol Sin. 2023 Oct;38(5):778-786
IPI-2I cells
40 μM
24 h
Evaluate the toxicity of CP-724714 on IPI-2I cells, showing no significant toxicity at concentrations below 40 μmol/L
Virol Sin. 2023 Oct;38(5):778-786
Vero cells
40 μM
24 h
Evaluate the toxicity of CP-724714 on Vero cells, showing no significant toxicity at concentrations below 40 μmol/L
Virol Sin. 2023 Oct;38(5):778-786
human neutrophils
10 μM
6 h
accelerated neutrophil apoptosis
Elife. 2019 Oct 15;8:e50990
HaCaT cells
5 µM
1 h
To investigate the effect of CP-724714 on Akt and ERK phosphorylation. Results showed that 5 µM CP-724714 significantly reduced phosphorylation levels of Akt and ERK.
Front Immunol. 2024 Feb 2;15:1335302.
HaCaT cells
2.5 µM
1 h
To investigate the inhibitory effect of CP-724714 on ErbB2 phosphorylation. Results showed that 2.5 µM CP-724714 significantly inhibited phosphorylation of ErbB2 at Y877 site.
Front Immunol. 2024 Feb 2;15:1335302.
HaCaT cells
5 µM
1 h
To investigate the inhibitory effect of CP-724714 on ErbB2 phosphorylation. Results showed that 5 µM CP-724714 significantly inhibited phosphorylation of ErbB2 at Y1221/1222 sites.
Front Immunol. 2024 Feb 2;15:1335302.
CP-724714 动物实验
Species
Animal Model
Administration
Dosage
Frequency
Description
References
Zebrafish
Tail fin injury inflammation model
Immersion
10 μM
16-hour pretreatment before injury
Reduced neutrophil number at the injury site
Elife. 2019 Oct 15;8:e50990
CP-724714 动物研究
Dose
Mice[1] (p.o.): min = 3.125 mg/kg, max = 100 mg/kg
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