GDC-0941
GDC-0941 is a novel selective class I phosphatidylinositol-3-kinase (PI3K) inhibitor. Activation of PI3K/Akt signaling pathway is frequently associated with tumorigenesis. Deregulation of this pathway occurs frequently with a variety of cancers and may contribute to the resistance to many anticancer agents. [1] Developing novel small molecules that specifically block the PI3K/Akt pathway may inhibit tumor growth. GDC-0941 is designed to bind the ATP-binding pocket of PI3K and to prevent formation of phosphatidylinositol-3, 4, 5-triphosphate (PIP3), a second messenger that transmits PI3K downstream signals. [2, 3] It binds to PI3K in an ATP-competitive manner.
GDC-0941 is a potent small-molecule thieno [3, 2-d] pyrimidine inhibitor of the class I PI3K. It is highly selective against isoforms p110( and p110( with IC50 of 3 nM, and moderately selective against isoforms p110( and p110( with IC50s of 33 nM and 75 nM, respectively.
GDC-0941 inhibits cell proliferation in vitro and in vivo. It causes growth inhibition in a variety of cancer cell lines, including A2780, MDA-MB-361, PC3, and U87MG. [2] It also inhibits the growth of trastuzumab–sensitive and –resistant HER2-amplied cancer cells which harbor p110( mutations or PTEN loss. [4] GDC-0941 also reduces tumor volume in different xenograft models. [4]
GDC-0941 can be taken orally.
References:
[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
- 2. Wenxiu Liu, Hongyan Gou, et al. "TTPAL promotes gastric tumorigenesis by directly targeting NNMT to activate PI3K/AKT signaling." Oncogene. 2021 Dec;40(49):6666-6679. PMID: 34642500
- 3. He L, Zhu W, et al. "Ovarian cancer cell-secreted exosomal miR-205 promotes metastasis by inducing angiogenesis." Theranostics. 2019 Oct 18;9(26):8206-8220. PMID: 31754391
- 4. 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
- 5. 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
- 6. 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
- 7. 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
- 8. 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
- 9. 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
- 10. Tian C, Yuan Z, et al. "Inhibition of glycolysis by a novel EGFR/HER2 inhibitor KU004 suppresses the growth of HER2+cancer." Exp Cell Res. 2017 May 19. pii: S0014-4827(17)30297-5. PMID: 28532652
- 11. Sabha N, Volpatti JR, et al. "PIK3C2B inhibition improves function and prolongs survival in myotubular myopathy animal models." J Clin Invest. 2016 Sep 1;126(9):3613-25. PMID: 27548528
- 12. 2016 Jun 21;28(9):1422-1431. PMID: 27339033
- 13. 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
- 14. Dr.Alvaro Diaz. "Condicionamiento de células dendríticas por la capa laminar de Echinococcus granulosus: búsqueda de agonistas y mecanismos a nivel de se?alizacón." colibri.udelar.edu.uy.2016.
- 15. Lindblad, Oscar, et al. "PI3 kinase is indispensable for oncogenic transformation by the V560D mutant of c-Kit in a kinase-independent manner." Cellular and Molecular Life Sciences (2015): 1-9. PMID: 26040420
| 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 |
| Shipping Condition | Small Molecules with Blue Ice, Modified Nucleotides with Dry Ice. |
| General tips | We do not recommend long-term storage for the solution, please use it up soon. |
| Cell experiment [1]: | |
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Cell lines |
Trastuzumab-Sensitive and -Insensitive HER2-Amplified Cells |
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Preparation method |
Limited solubility. General tips for obtaining a higher concentration: Please warm the tube at 37 ℃ for 10 minutes and/or shake it in the ultrasonic bath for a while. Stock solution can be stored below -20℃ for several months. |
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Reaction Conditions |
2 h |
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Applications |
250 nM GDC-0941 treatment for 2 hours leads to 40%–85% inhibition of pAKT in all cell lines tested. GDC-0941 also inhibits the PI3K/AKT pathway by reducing cell proliferation/viability in a dose dependent manner. GDC-0941 inhibits the growth of both trastuzumab-sensitive and -insensitive cells. |
| Animal experiment [2]: | |
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Animal models |
U87MG human glioblastoma xenografts |
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Dosage form |
Orally at 75 mg/kg daily |
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Applications |
GDC-0941 inhibits the tumor growth by 83% after 21 days with no body weight loss. A dose-response relationship is also observed over the range 25-150 mg/kg/day. GDC-0941 also decreases the p-Akt levels as an indication of target inhibition. |
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Other notes |
Please test the solubility of all compounds indoor, and the actual solubility may slightly differ with the theoretical value. This is caused by an experimental system error and it is normal. |
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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. |
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| Description | GDC-0941 is a potent inhibitor of PI3Kα/δ with IC50 of 3 nM, with modest selectivity against p110β (11-fold) and p110γ (25-fold). | |||||
| Targets | PI3Kα | PI3Kβ | PI3Kδ | PI3Kγ | ||
| IC50 | 3 nM | 33 nM | 3 nM | 75 nM | ||
Quality Control & MSDS
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