27 research outputs found
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An inhibitor of oxidative phosphorylation exploits cancer vulnerability.
Get PDFMetabolic reprograming is an emerging hallmark of tumor biology and an actively pursued opportunity in discovery of oncology drugs. Extensive efforts have focused on therapeutic targeting of glycolysis, whereas drugging mitochondrial oxidative phosphorylation (OXPHOS) has remained largely unexplored, partly owing to an incomplete understanding of tumor contexts in which OXPHOS is essential. Here, we report the discovery of IACS-010759, a clinical-grade small-molecule inhibitor of complex I of the mitochondrial electron transport chain. Treatment with IACS-010759 robustly inhibited proliferation and induced apoptosis in models of brain cancer and acute myeloid leukemia (AML) reliant on OXPHOS, likely owing to a combination of energy depletion and reduced aspartate production that leads to impaired nucleotide biosynthesis. In models of brain cancer and AML, tumor growth was potently inhibited in vivo following IACS-010759 treatment at well-tolerated doses. IACS-010759 is currently being evaluated in phase 1 clinical trials in relapsed/refractory AML and solid tumors
La meccanica del confine
No full textIl volume, che prende le mosse da un ciclo di seminari tenutosi all\u2019Universit\ue0 Ca\u2019 Foscari Venezia, si propone un\u2019esplorazione delle opportunit\ue0 euristiche legate al concetto di confine. Raccogliendo tredici contributi afferenti ad ambiti disciplinari diversi e organizzati in quattro sezioni tematiche, nel suo complesso esso ambisce a mostrare l\u2019arbitrariet\ue0 sottesa al tracciamento di ogni confine e a far luce sulla meccanica che orienta i processi di partizion
N-​(4-​Fluorobenzyl)​-​3-​hydroxy-​9,​9-​dimethyl-​4-​oxo-​6,​7,​8,​9-​tetrahydro-​4H-​pyrazino[1,​2-​a]​pyrimidine-​2-​carboxamides a novel class of potent HIV-​1 integrase inhibitors
No full textFrom dihydroxypyrimidine carboxylic acids to carboxamide HIV-​1 integrase inhibitors: SAR around the amide moiety
No full textFused pyrimidinones as HIV integrase inhibitors and their preparation and use in the treatment of HIV infection
No full textHCV NS5b RNA-​Dependent RNA Polymerase Inhibitors: From α,​γ-​Diketoacids to 4,​5-​Dihydroxypyrimidine- or 3-​Methyl-​5- hydroxypyrimidinonecarboxylic Acids. Design and Synthesis
No full textDiscovery of α,​γ-​Diketo Acids as Potent Selective and Reversible Inhibitors of Hepatitis C Virus NS5b RNA-​Dependent RNA Polymerase
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