GDC-0941
mRNA synthesis
In vitro transcription of capped mRNA with modified nucleotides and Poly(A) tail
Tyramide Signal Amplification (TSA)
TSA (Tyramide Signal Amplification), used for signal amplification of ISH, IHC and IC etc.
Phos Binding Reagent Acrylamide
Separation of phosphorylated and non-phosphorylated proteins without phospho-specific antibody
Cell Counting Kit-8 (CCK-8)
A convenient and sensitive way for cell proliferation assay and cytotoxicity assay
SYBR Safe DNA Gel Stain
Safe and sensitive stain for visualization of DNA or RNA in agarose or acrylamide gels.
Inhibitor Cocktails
Protect the integrity of proteins from multiple proteases and phosphatases for different applications.
GDC-0941是一种新型的选择性I类磷脂酰肌醇3-激酶（PI3K）抑制剂。PI3K / Akt信号途径的活化经常与肿瘤的发生有关，该途径的失调经常发生在各种癌症中，可能造成对许多抗癌剂的耐受性[1]。因而，开发的新型可特异性阻断PI3K / Akt通路的小分子可以抑制肿瘤生长。GDC-0941竞争性地与PI3K的ATP结合口袋相结合，阻止传递PI3K下游信号的第二信使磷脂酰肌醇3，4，5-三磷酸（PIP 3）的形成[2, 3]。
GDC-0941是一种有效的I类PI3K小分子抑制剂，属于噻吩并[3，2-d]嘧啶类化合物。GDC-0941对p110α/δ具有高度选择性，IC50值为3 nM。对p110β和p110γ具有适度的选择性，IC50值分别为33 nM和75 nM。
GDC-0941在体外和体内均可抑制细胞增殖。在多个肿瘤细胞系中，包括A2780、MDA-MB-361、PC3和U87MG，GDC-0941引起生长抑制[2]。GDC-0941也可以抑制含有p110突变或PTEN缺失的trastuzumab敏感或抗性的HER2扩增癌细胞的生长。在多个异种移植肿瘤模型中，GDC-0941也可以减少肿瘤体积[4]。GDC-0941是可口服的。
参考文献：
[1]Yuan TL, Cantley LC. PI3K pathway alterations in cancer: variations on a theme. Oncogene. 2008;27:5497-5510.
[2]Folkes AJ, Ahmadi K, Alderton WK, et al. The identification of 2-(1H-Indazol-4-yl)-6-(4-methanesulfonyl-piperazin-1-ylmethyl)-4-morpholin-4-yl-thieno[3,2-d]pyrimidine (GDC-0941) as a potent, selective, orally bioavailable inhibitor of class I PI3 kinase for the treatment of cancer. J Med Chem. 2008; 51: 5522-5532.
[3]Knight ZA, Shokat KM. Chemically targeting the PI3K family. Biochem Soc Trans. 2007; 35: 245-249.
[4]Junttila TT, Akita RW, Parsons K, Fields C, Lewis Phillips GD, Friedman LS, Sampath D, Sliwkowski MX. Ligand-independent HER2/HER3/PI3K complex is disrupted by trastuzumab and is effectively inhibited by the PI3K inhibitor GDC-0941. Br J Cancer. 2011; 104(7): 1116-25.
- 1. York Posor, Charis Kampyli, et al. "Local synthesis of the phosphatidylinositol-3, 4-bisphosphate lipid drives focal adhesion turnover." Dev Cell. 2022 Jul 25;57(14):1694-1711.e7. PMID: 35809565
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- 3. Pittini Á, Martínez-Acosta YE, et al. "Particles from the Echinococcus granulosus laminated layer inhibit CD40 upregulation in dendritic cells by interfering with Akt activation." Infect Immun. 2019 Sep 30. pii: IAI.00641-19. PMID: 31570562
- 4. Chen H, Wong CC, et al. "APLN promotes hepatocellular carcinoma through activating PI3K/Akt pathway and is a druggable target." Theranostics. 2019 Jul 9;9(18):5246-5260. PMID: 31410213
- 5. Iniguez AB, Alexe G, et al. "Resistance to Epigenetic-Targeted Therapy Engenders Tumor Cell Vulnerabilities Associated with Enhancer Remodeling." Cancer Cell. 2018 Dec 10;34(6):922-938.e7. PMID: 30537514
- 6. Jiang H, Xu M, et al. "Concurrent HER or PI3K Inhibition Potentiates the Anti-tumor Effect of ERK Inhibitor Ulixertinib in Preclinical Pancreatic Cancer Models." Mol Cancer Ther. 2018 Jul 31. pii: molcanther.1142.2017. PMID: 30065098
- 7. Wang YN, Lee HH, et al. "Angiogenin/Ribonuclease 5 Is an EGFR Ligand and a Serum Biomarker for Erlotinib Sensitivity in Pancreatic Cancer." Cancer Cell. 2018 Apr 9;33(4):752-769.e8. PMID: 29606349
- 8. Zhang X, Zhao F, et al. "PDGF-mediated PI3K/AKT/β-catenin signaling regulates gap junctions in corpus cavernosum smooth muscle cells." Exp Cell Res. 2017 Nov 22. pii: S0014-4827(17)30627-4. PMID: 29174980
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- 11.Tsioumpekou M, Papadopoulos N, et al."Platelet-derived growth factor (PDGF)-induced activation of Erk5 MAP-kinase is dependent on Mekk2, Mek1/2, PKC and PI3-kinase, and affects BMP signaling." Cell Signal. 2016 Jun 21;28(9):1422-1431. PMID: 27339033
- 12. Pittini Á, Casaravilla C, et al. "Pharmacological inhibition of PI3K class III enhances the production of pro- and anti-inflammatory cytokines in dendritic cells stimulated by TLR agonists." Int Immunopharmacol. 2016 May 8;36:213-217. PMID: 27168056
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| Physical Appearance | A solid |
| Storage | Store at -20°C |
| M.Wt | 513.64 |
| Cas No. | 957054-30-7 |
| Formula | C23H27N7O3S2 |
| Solubility | ≥25.7 mg/mL in DMSO; insoluble in H2O; ≥3.59 mg/mL in EtOH with gentle warming and ultrasonic |
| Chemical Name | 4-[2-(1H-indazol-4-yl)-6-[(4-methylsulfonylpiperazin-1-yl)methyl]thieno[3,2-d]pyrimidin-4-yl]morpholine |
| SDF | Download SDF |
| Canonical SMILES | CS(=O)(=O)N1CCN(CC1)CC2=CC3=C(S2)C(=NC(=N3)C4=C5C=NNC5=CC=C4)N6CCOCC6 |
| 运输条件 | 蓝冰运输或根据您的需求运输。 |
| 一般建议 | 不同厂家不同批次产品溶解度各有差异，仅做参考。若实验所需浓度过大至产品溶解极限，请添加助溶剂助溶或自行调整浓度。溶液形式一般不宜长期储存，请尽快用完。 |
| 细胞实验[1]: | |
|
细胞系 |
Trastuzumab敏感和不敏感的HER2扩增细胞 |
|
制备方法 |
溶解度有限。若配制更高浓度的溶液，一般步骤如下：请将试管置于37℃加热10分钟和/或将其置于超声波浴中震荡一段时间。原液于-20℃可放置数月。 |
|
反应条件 |
2 h |
|
实验结果 |
在所测试的所有细胞系中，250 nM GDC-0941处理2小时，抑制40％-85％的pAKT。GDC-0941还以剂量依赖性方式通过降低细胞增殖/活力来抑制PI3K/AKT途径。GDC-0941抑制trastuzumab敏感和不敏感的细胞生长。 |
| 动物实验[2]: | |
|
动物模型 |
U87MG人胶质母细胞瘤异种移植物 |
|
给药剂量 |
口服，每天75 mg/kg |
|
实验结果 |
给药21天后，GDC-0941在不影响体重的情况下抑制83％肿瘤生长。剂量范围25-150 mg/kg/day的GDC-0941给药观察到剂量反应关系。GDC-0941还降低作为靶抑制指示剂的p-Akt水平。 |
|
注意事项 |
请于室内测试所有化合物的溶解度。虽然化合物的实际溶解度可能与其理论值略有不同，但仍处于实验系统误差的允许范围内。 |
|
References: 1. Junttila TT, Akita RW, Parsons K et al. Ligand-independent HER2/HER3/PI3K complex is disrupted by trastuzumab and is effectively inhibited by the PI3K inhibitor GDC-0941. Cancer Cell. 2009 May 5;15(5):429-40. 2. Folkes AJ, Ahmadi K, Alderton WK et al. The identification of 2-(1H-indazol-4-yl)-6-(4-methanesulfonyl-piperazin-1-ylmethyl)-4-morpholin-4-yl-t hieno[3,2-d]pyrimidine (GDC-0941) as a potent, selective, orally bioavailable inhibitor of class I PI3 kinase for the treatment of cancer . J Med Chem. 2008 Sep 25;51(18):5522-32. |
|
| 描述 | GDC-0941是一种有效的PI3Kα/δ抑制剂，IC50值为3 nM，对p110β (11倍)和p110γ (25倍)具有适度的选择性。 | |||||
| 靶点 | PI3Kα | PI3Kβ | PI3Kδ | PI3Kγ | ||
| IC50 | 3 nM | 33 nM | 3 nM | 75 nM | ||
质量控制和MSDS
- 批次:
化学结构
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