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- W2076352308 abstract "Proceedings: AACR 104th Annual Meeting 2013; Apr 6-10, 2013; Washington, DCMetabolic plasticity is an adaptive mechanism tumors rely upon for growth advantage. Without sufficient energy and biomass, cell replication cannot proceed. Therefore, interrupting cancer-specific metabolic processes presents a novel means to inhibit tumor growth. The clinical benefit of this approach has not yet been fully realized due to a lack of suitable agents targeting cancer cell metabolism. To address this unmet need we screened our in-house compound library for chemical scaffolds with potential metabolic activity. In the course of our studies we identified the small molecule AV220 as a potent metabolic antagonist suitable for preclinical development. In a panel of cancer cell lines, AV220 showed anti-proliferative activity in the low micromolar range. Mechanistic studies indicate a mode of action that involves energy sensing and regulatory pathways. AV220 treatment produced a rapid and sustained phosphorylation of AMPK and its substrate acetyl-CoA carboxylase. Prolonged treatment with AV220 resulted in profound intracellular vacuolation and increased autophagic flux followed by accumulation of Grp78, CHOP and ATF4. Additional early intracellular signaling events associated with AV220 treatment included phosphorylation of p38 and Erk 1/2 and Src and Akt inhibition. A structure-based search of our small molecule library led to the identification of additional analogs, many of which displayed similar cytotoxicities and a shared mechanism of action.Citation Format: Melissa Millard, Nouri Neamati. Discovery and mechanistic characterization of AV220, a novel small molecule targeting cancer cell metabolism. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2480. doi:10.1158/1538-7445.AM2013-2480" @default.
- W2076352308 created "2016-06-24" @default.
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- W2076352308 date "2013-04-15" @default.
- W2076352308 modified "2023-09-27" @default.
- W2076352308 title "Abstract 2480: Discovery and mechanistic characterization of AV220, a novel small molecule targeting cancer cell metabolism." @default.
- W2076352308 doi "https://doi.org/10.1158/1538-7445.am2013-2480" @default.
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