Oncogenic KRAS sensitizes lung adenocarcinoma to GSK-J4-lnduced metabolic and oxidative stress was written by Hong, Beom-Jin;Park, Woo-Yong;Kim, Hwa-Ryeon;Moon, Jin Woo;Lee, Ho Yeon;Park, Jun Hyung;Kim, Seon-Kyu;Oh, Youngbin;Roe, Jae-Seok;Kim, Mi-Young. And the article was included in Cancer Research in 2019.Formula: C24H27N5O2 The following contents are mentioned in the article:
Genetic and epigenetic changes (e.g., histone methylation) contribute to cancer development and progression, but our understanding ofwhether and how specific mutations affect a cancer’s sensitivity to histone demethylase (KDM) inhibitors is limited. Here, we evaluated the effects of a panel of KDM inhibitors on lung adenocarcinomas (LuAC) with various mutations. Notably, LuAC lines harboring KRAS mutations showed hypersensitivity to the histone H3K27 demethylase inhibitor GSK-J4. Specifically, GSK-J4 treatment of KRAS mutant-containing LuAC downregulated cell-cycle progression genes with increased H3K27me3. In addition, GSK-J4 upregulaled expression of genes involved in glutamine/ glutamate transport and metabolism In line with this, GSK-J4 reduced cellular levels ofglutamate, a key source oftheTCA cycle intermediate α-ketogluiarate (αKG) and of the antioxidant glutathione, leading to reduced cell viability. Supplementation with an αKG analog or glutathione protected KRAS-mutant LuAC cells from GSK-J4-mediaied reductions in viability, suggesting GSK-J4 exerts its anticancer effects by inducing metabolic and oxidative stress. Importantly, KRAS knockdown in mutant LuAC lines prevented GSK-J4-induced decrease in glutamate levels and reduced their susceptibility to GSK-J4, whereas overexpression ofoncogenic KRAS in wildtype LuAC lines sensitized them to GSK-J4- Collectively, our study uncovers a novel association between a genetic mutation and KDM inhibitor sensitivity and identifies the underlying mechanisms. This suggests GSK-J4 as a potential treatment option for cancer patients with KRAS mutations. This study involved multiple reactions and reactants, such as Ethyl 3-((6-(4,5-dihydro-1H-benzo[d]azepin-3(2H)-yl)-2-(pyridin-2-yl)pyrimidin-4-yl)amino)propanoate (cas: 1373423-53-0Formula: C24H27N5O2).
Ethyl 3-((6-(4,5-dihydro-1H-benzo[d]azepin-3(2H)-yl)-2-(pyridin-2-yl)pyrimidin-4-yl)amino)propanoate (cas: 1373423-53-0) belongs to pyrimidine derivatives. Heterocyclic compounds bearing the pyrimidine core are of tremendous interest as they constitute an important class of natural and synthetic compounds exhibiting diverse useful biological activities that hold attractive potential for clinical translation as therapeutic agents in alleviation of a myriad of diseases. A Cu-catalyzed and 4-HO-TEMPO-mediated [3 + 3] annulation of commercially available amidines with saturated ketones enables an efficient and facile synthesis of structurally important pyrimidines via a cascade reaction of oxidative dehydrogenation/annulation/oxidative aromatization.Formula: C24H27N5O2
Referemce:
Pyrimidine | C4H4N2 – PubChem,
Pyrimidine – Wikipedia