A pan inhibitor of class I PI3K isoforms
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.
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.
| 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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参考文献: 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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