生物活性
GDC-0941是一种有效的PI3Kα/δ抑制剂，IC50为3 nM，比对p110β(10倍)和p110γ的作用强25倍。GDC-0941也等效作用于PI3Kα和 PI3Kδ和PI3Kα突变型E545-K和H1047-R,也选择性作用于PI3Kβ(10倍)和 PI3Kγ(25倍), 选择性更高地作用于PI3K II, III, 和IV类成员，包括, C2β, Vps34, DNA-PK和mTOR。GDC-0941 作用于U87MG, PC3, 和 MDA-MB-361 细胞，有效抑制Akt磷酸化，IC50分别为46 nM, 37 nM,和 28 nM。GDC-0941抑制U87MG, A2780, PC3, 和MDA-MB-361细胞增殖，IC50分别为 0.95 μM, 0.14 μM, 0.28 μM, 和0.72 μM。
使用AbMole产品发表的文献
产品使用成果展示
 |
数据来源 |
Journal of Nuclear Medicine (2018 Nov). Figure 3. GDC-0941 (AbMole Bioscience Inc.) |
| 方法 |
oral gavage |
| 细胞系/动物模型 |
single mutant BRAFV600E mice |
| 浓度 |
50 mg/kg |
| 处理时间 |
10 days |
| 实验结果 |
The selective BRAFV600E inhibitor PLX-4720 did not increase Nis mRNA transcription, nor did the PI3K inhibitor GDC-0941 alone or in combination with PD-325901 or PLX-4720. |
 |
数据来源 |
Journal of Experimental & Clinical Cancer Research (2018). Figure 4. GDC-0941 (Abmole Bioscience) |
| 方法 |
oral gavage |
| 细胞系/动物模型 |
BRAFV600E/PIK3CAH1047R double-mutant mouse |
| 浓度 |
50 mg/kg |
| 处理时间 |
10 days |
| 实验结果 |
While Pi3K inhibition did not induced any change in Slc7a5 transcript abundance, MEK inhibition induced more than 50% reduction. |
 |
数据来源 |
Molecular Cancer Research (2018). Figure 2. GDC-0941 (Abmole Bioscience) |
| 方法 |
cell viability assay |
| 细胞系/动物模型 |
M-SCC-14A, UM-SCC-14B, and UM-SCC-14C cells |
| 浓度 |
|
| 处理时间 |
72 hours |
| 实验结果 |
Interestingly, pictilisib was less effective at impairing proliferation in UM-SCC-14B than in the other two matched cell lines. |
 |
数据来源 |
BioRxiv (2017). Figure 6. GDC-0941 (Abmole Bioscience, Hong-Kong, China) |
| 方法 |
western blot |
| 细胞系/动物模型 |
8505c cells |
| 浓度 |
1 μM |
| 处理时间 |
|
| 实验结果 |
Paradoxical ERK hyperphosphorylation was not detectable when cells were subjected to GDC-0941 in addition to PLX-4032 drug dilutions. When we treated them with the same concentrations of PLX-4032, 8505c and SW1736 cells did not exhibit paradoxical ERK activation. |
 |
数据来源 |
BioRxiv (2017). Figure 4. GDC-0941 (Abmole Bioscience, Hong-Kong, China) |
| 方法 |
paradoxical activation |
| 细胞系/动物模型 |
Thyroglobulin Cre ERT2 mice |
| 浓度 |
50 mg/kg |
| 处理时间 |
10 d |
| 实验结果 |
Only GDC-0941 and drug combination treated animals showed tumor burden reduction. PLX-4720 treated animals displayed an elevation in tumor burden that was not statistically different from the controls but from the two other groups. |
 |
数据来源 |
BioRxiv (2017). Figure 3. GDC-0941 (Abmole Bioscience, Hong-Kong, China) |
| 方法 |
paradoxical activation |
| 细胞系/动物模型 |
Thyroglobulin Cre ERT2 mice |
| 浓度 |
50 mg/kg |
| 处理时间 |
70 d |
| 实验结果 |
When treated with drug combination, ERK paradoxical activation was abolished resulting in ERK phosphorylation level comparable to controls. AKT phosphorylation was not affected by PLX-4720 while GDC-0941 treatment resulted in a small but significant reduction of AKT phosphorylation. |
 |
数据来源 |
BioRxiv (2017). Figure 2. GDC-0941 (Abmole Bioscience, Hong-Kong, China) |
| 方法 |
Histological presentation |
| 细胞系/动物模型 |
Thyroglobulin Cre ERT2 mice |
| 浓度 |
50 mg/kg |
| 处理时间 |
70 d |
| 实验结果 |
GDC-0941-treated mice had smaller thyroid sections, while presenting a similar histology compared to controls (Fig. 2B) with a mixture of PTC containing small ATC foci. |
 |
数据来源 |
BioRxiv (2017). Figure 1. GDC-0941 (Abmole Bioscience, Hong-Kong, China) |
| 方法 |
tumor burden assay |
| 细胞系/动物模型 |
Thyroglobulin Cre ERT2 mice |
| 浓度 |
50 mg/kg |
| 处理时间 |
70 d |
| 实验结果 |
GDC-0941 treated animals presented an initial tumor burden reduction of 20% then tumor size stabilized for the rest of the treatment period. Interestingly, when a drug combination of PLX-4720 and GDC-0941 was administered, mice showed a robust response with 60% lower tumor burden after 6 weeks followed by stabilization until the end of the experiment. |
.figure 4..jpg) |
数据来源 |
Oncotarget (2017). GDC-0941, Figure 4. (AbMole Bioscience, Hong-Kong, China) |
| 方法 |
Western blot |
| 细胞系/动物模型 |
ATC cell |
| 浓度 |
50 mg/kg |
| 处理时间 |
24 h |
| 实验结果 |
Interestingly, PD-325901 treated mice showed a clear improvement in histology with some almost normal follicles and smaller PTC areas. GDC-0941 did not induce a beneficial effect at the histological level. Finally, mice treated with the combination, although resulting in smaller sections, seemed to have a similar histological presentation to PD-325901 alone treated animals (Figure 4C). |
.figure 3..jpg) |
数据来源 |
Oncotarget (2017). GDC-0941, Figure 3. (AbMole Bioscience, Hong-Kong, China) |
| 方法 |
Western blot |
| 细胞系/动物模型 |
ATC cell |
| 浓度 |
|
| 处理时间 |
24 h |
| 实验结果 |
ERK1/2 and AKT phosphorylation were assessed first to demonstrate the drug efficiency. ERK1/2 phosphorylation ratio (p-ERK1/2 normalized to total ERK) was strongly decreased in all cell lines when treated with PD-325901 alone or in combination with GDC-0941. Similarly, GDC-0941 induced a strong reduction of AKT phosphorylation ratio (Figure 3). |
.figure 2..jpg) |
数据来源 |
Oncotarget (2017). GDC-0941, Figure 2. (AbMole Bioscience, Hong-Kong, China) |
| 方法 |
apoptosis assay |
| 细胞系/动物模型 |
OCUT-2 cells |
| 浓度 |
1 μM |
| 处理时间 |
24 h |
| 实验结果 |
Only the OCUT-2 cell line already showed increased apoptosis (double positive annexinV and PI cells) when treated with the combination for 24 h (Figure 2A). However, after 48 h of combination treatment, all three cell lines (Figure 2B and Supplementary Figure 1) had elevated double positive annexinV/PI cells (late apoptosis) and annexinV positive cells (early apoptosis). |
.figure 1..jpg) |
数据来源 |
Oncotarget (2017). GDC-0941, Figure 1. (AbMole Bioscience, Hong-Kong, China) |
| 方法 |
|
| 细胞系/动物模型 |
SW1736 and OCUT-2 cell lines |
| 浓度 |
2 μM, 400 nM, 80 nM, 16 nM, 3.2 nM |
| 处理时间 |
72 h |
| 实验结果 |
We investigated the effect of the drugs on cell cycling. PD-325901 alone or in combination with GDC-0941 induced a G1 cycle arrest in SW1736 and 8505c cell lines. However, in OCUT-2, a significant effect was only observed for the combination (Figure 1C). |
. gdc-0941, figure 5.jpg) |
数据来源 |
Mol Cancer (2017). GDC-0941, Figure 5. (AbMole BioScience, Hongkong, China) |
| 方法 |
cell proliferation assay |
| 细胞系/动物模型 |
NIH3T3 cells |
| 浓度 |
0-100 nM |
| 处理时间 |
16 h |
| 实验结果 |
Combination treatment led to more effective abrogation of AKT phosphorylation than either tepotinib or pictilisib alone, but p-S6 levels were generally unaltered (Fig. 5b). |
. gdc-0941, figure 4.jpg) |
数据来源 |
Mol Cancer (2017). GDC-0941, Figure 4. (AbMole BioScience, Hongkong, China) |
| 方法 |
In vivo tumor growth delay experiments |
| 细胞系/动物模型 |
|
| 浓度 |
50 mg/kg |
| 处理时间 |
5 d |
| 实验结果 |
Comparison of average tumor sizes of vector vs. H1047R at the experimental endpoint showed significant resistance to tepotinib in H1047R tumors (p = 0.012), as well as higher efficacy of pictilisib in the same group (p = 0.026; Fig. 4d). |
. gdc-0941, figure 1.jpg) |
数据来源 |
Mol Cancer (2017). GDC-0941, Figure 1. (AbMole BioScience, Hongkong, China) |
| 方法 |
Cell viability/toxicity assays |
| 细胞系/动物模型 |
NIH3T3 cells |
| 浓度 |
0-100 nM |
| 处理时间 |
16 h |
| 实验结果 |
PI3K inhibition by pictilisib was similarly effective in reducing p-AKT levels in these three cell lines, but at a concentration of 100 nM p-S6 levels were lower in cells harboring PIK3CA mutations (Fig. 1b). |
实验参考
| 体外实验* |
|---|
| 细胞系 |
U87MG cell line |
| 方法 |
Proliferation Assay. The human tumor cell lines used wereobtained from the ATCC. Cells were plated at 4 × 104 cells/ mL and cultured at 37 °C with 5% CO2 in DMEM supplemented with 10% fetal calf serum, and L-glutamine. Test compound was added to replicate wells in a volume of 10 µL such that the final DMSO concentration did not exceed 0.2%. After 4 days of incubation, 10 µL of Alamar Blue reagent was added and developed for 6 h at 37 °C before measuring the fluorescence excitation/emission (wavelength 540/595 nm) using a Victor plate reader. The reported IC50 values are means of at least two independent experiments with variations of less than 20%.
|
| 浓度 |
0~10µM |
| 处理时间 |
4 days |
*上述方法来自公开文献，仅供相同目的实验参考。如实验目的、材料、方法不同，请参考其他文献。
| 体内实验* |
|---|
| 动物模型 |
Human tumor xenografts of U87MG glioblastoma of female NCr athymic mice |
| 配制 |
10% DMSO, 5% Tween 20, 85% water |
| 剂量 |
75 mg/kg once daily |
| 给药处理 |
oral gavage |
*上述方法来自公开文献，仅供相同目的实验参考。如实验目的、材料、方法不同，请参考其他文献。
化学性质
| 分子量 |
513.64 |
| 分子式 |
C23H27N7O3S2 |
| CAS号 |
957054-30-7
|
| 溶解性（25°C） |
DMSO 40 mg/mL |
| 储存条件 |
粉末型式 -20°C 3年；4°C 2年
溶于溶剂 -80°C 6个月；-20°C 1个月
|
| 运输方式 |
冰袋运输，根据产品的不同，可能会有相应调整。 |
储备液配制
*下述溶液配置方法仅为基于分子量计算出的理论值。不同产品在配置溶液前，需考虑其在不同溶剂中的溶解度限制。
| Concentration / Solvent Volume / Mass |
1 mg |
5 mg |
10 mg |
| 1 mM |
1.9469 mL |
9.7344 mL |
19.4689 mL |
| 5 mM |
0.3894 mL |
1.9469 mL |
3.8938 mL |
| 10 mM |
0.1947 mL |
0.9734 mL |
1.9469 mL |
不同实验动物依据体表面积的等效剂量转换表（参考来源于公开文献）
|
小鼠 |
大鼠 |
兔 |
豚鼠 |
仓鼠 |
狗 |
| 重量 (kg) |
0.02 |
0.15 |
1.8 |
0.4 |
0.08 |
10 |
| 体表面积 (m2) |
0.007 |
0.025 |
0.15 |
0.05 |
0.02 |
0.5 |
| Km 系数 |
3 |
6 |
12 |
8 |
5 |
20 |
| 动物 A (mg/kg) = 动物 B (mg/kg) × |
动物 B的Km系数
|
| 动物 A的Km系数 |
例如，依据体表面积折算法，将化合物用于小鼠的剂量20 mg/kg 换算成大鼠的剂量，需要将20 mg/kg 乘以小鼠的Km系数（3），再除以大鼠的Km系数（6），得到化合物用于大鼠的等效剂量为10 mg/kg。
参考文献
[1] Nishida et al. Hypertension. Phosphatidylinositol 3-Kinase/Akt Signaling Pathway Activates the WNK-OSR1/SPAK-NCC Phosphorylation Cascade in Hyperinsulinemic db/db Mice.
[2] Bressanin et al. Oncotarget. Harnessing the PI3K/Akt/mTOR pathway in T-cell acute lymphoblastic leukemia: Eliminating activity by targeting at different levels.
[3] Zhu et al. Chem Pharm Bull (Tokyo). Design, Synthesis and Anticancer Activity of 4-Morpholinothieno[3,2-d]pyrimidine Derivatives Bearing Arylmethylene Hydrazine Moiety.
[4] Wallin et al. Clin Cancer Res. GDC-0941, a novel class I selective PI3K inhibitor, enhances the efficacy of docetaxel in human breast cancer models by increasing cell death in vitro and in vivo.
[5] Foreman et al. Mol Cancer Ther. ErbB3 inhibitory surrobodies inhibit tumor cell proliferation in vitro and in vivo.
蛋白质研究