CVT-11127
(Synonyms: GS-456332) 目录号 : GC66005CVT-11127 (FMK13918) is an inhibitor of stearoylCoA desaturase-1 (SCD1). CVT-11127 reduces lipid synthesis and impaires proliferation by blocking the progression of cell cycle through the G(1)/S boundary and by triggering programmed cell death.
Cas No.:1018674-83-3
Sample solution is provided at 25 µL, 10mM.
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CVT-11127 (FMK13918) is an inhibitor of stearoylCoA desaturase-1 (SCD1). CVT-11127 reduces lipid synthesis and impaires proliferation by blocking the progression of cell cycle through the G(1)/S boundary and by triggering programmed cell death.
CVT-11127, an SCD1 inhibitor, decreases expression of SCD1, prevents the growth of STK11/KEAP1 co-mutant cells and sensitizes those cells to ferroptosis induction.[2]
[1] Daniel Hess, et al. PLoS One. 2010 Jun 30;5(6):e11394. [2] Wohlhieter CA, et al. Cell Rep. 2020 Dec 1;33(9):108444.
Cas No. | 1018674-83-3 | SDF | Download SDF |
别名 | GS-456332 | ||
分子式 | C25H23Cl2N5O3 | 分子量 | 512.39 |
溶解度 | 储存条件 | Store at -20°C | |
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1 mg | 5 mg | 10 mg | |
1 mM | 1.9516 mL | 9.7582 mL | 19.5164 mL |
5 mM | 0.3903 mL | 1.9516 mL | 3.9033 mL |
10 mM | 0.1952 mL | 0.9758 mL | 1.9516 mL |
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Inhibition of stearoylCoA desaturase activity blocks cell cycle progression and induces programmed cell death in lung cancer cells
PLoS One 2010 Jun 30;5(6):e11394.PMID:20613975DOI:10.1371/journal.pone.0011394.
Lung cancer is the most frequent form of cancer. The survival rate for patients with metastatic lung cancer is approximately 5%, hence alternative therapeutic strategies to treat this disease are critically needed. Recent studies suggest that lipid biosynthetic pathways, particularly fatty acid synthesis and desaturation, are promising molecular targets for cancer therapy. We have previously reported that inhibition of stearoylCoA desaturase-1 (SCD1), the enzyme that produces monounsaturated fatty acids (MUFA), impairs lung cancer cell proliferation, survival and invasiveness, and dramatically reduces tumor formation in mice. In this report, we show that inhibition of SCD activity in human lung cancer cells with the small molecule SCD inhibitor CVT-11127 reduced lipid synthesis and impaired proliferation by blocking the progression of cell cycle through the G(1)/S boundary and by triggering programmed cell death. These alterations resulting from SCD blockade were fully reversed by either oleic (18:1n-9), palmitoleic acid (16:1n-7) or cis-vaccenic acid (18:1n-7) demonstrating that cis-MUFA are key molecules for cancer cell proliferation. Additionally, co-treatment of cells with CVT-11127 and CP-640186, a specific acetylCoA carboxylase (ACC) inhibitor, did not potentiate the growth inhibitory effect of these compounds, suggesting that inhibition of ACC or SCD1 affects a similar target critical for cell proliferation, likely MUFA, the common fatty acid product in the pathway. This hypothesis was further reinforced by the observation that exogenous oleic acid reverses the anti-growth effect of SCD and ACC inhibitors. Finally, exogenous oleic acid restored the globally decreased levels of cell lipids in cells undergoing a blockade of SCD activity, indicating that active lipid synthesis is required for the fatty acid-mediated restoration of proliferation in SCD1-inhibited cells. Altogether, these observations suggest that SCD1 controls cell cycle progression and apoptosis and, consequently, the overall rate of proliferation in cancer cells through MUFA-mediated activation of lipid synthesis.
Stearoyl-CoA desaturase activity modulates the activation of epidermal growth factor receptor in human lung cancer cells
Exp Biol Med (Maywood) 2012 Sep;237(9):1007-17.PMID:22946088DOI:10.1258/ebm.2012.012126.
Stearoyl-CoA desaturase-1 (SCD1), the main enzyme that converts saturated fatty acids into monounsaturated fatty acids, is a key factor in the mechanisms of cancer cell proliferation, survival and tumorigenesis. Evidence indicates that SCD1 activity regulates these events in part by targeting the phosphatidylinositol-3 phosphate kinase/Akt and Ras/extracellular signal-regulated kinase (ERK) pathways, but the molecular mechanisms remain unknown. We now show that in H460 lung cancer cells, the suppression of SCD activity with CVT-11127, a specific small molecule SCD inhibitor, impairs the ligand-induced phosphorylation of epidermal growth factor (EGF) receptor, causing the inactivation of its downstream targets Akt, ERK and mammalian target of rapamycin. Importantly, the mitogenic response to EGF was markedly defective in SCD-depleted cancer cells. The inactivation of EGF receptor (EGFR) promoted by SCD inhibition may be caused by perturbations in the lipid microenvironment surrounding the receptor, since we detected significant alterations in the lateral mobility of plasma lipid microdomains. Finally, incubation of lung cancer cells with SCD blockers potentiated the antigrowth effect of gefitinib, an EGFR inhibitor employed in cancer treatment. Altogether, our data indicate that SCD activity may control cancer cell metabolism, proliferation and survival by modulating the EGFR→Akt/ERK signaling platforms. Our studies also suggest a value for SCD inhibitors as novel pharmacological agents in lung cancer, one of the most common and lethal forms of cancer for which therapeutic options remain very limited.