Identification and validation of protein targets of bioactive small molecules

Titov, Denis V.; Liu, Jun O.

doi:10.1016/j.bmc.2011.11.070

Cited by 37 publications

(34 citation statements)

References 104 publications

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“…One way of determining the physiological relevance of a drug target is to see whether there is a pharmacological correlation between the binding of different analogs of the drug to the target and their cellular activity (38). As previously reported, miconazole, terconazole, and fluconazole have IC 50 values for HUVEC proliferation of about 2.5, 7, and >100 μM, respectively (8).…”

Section: Correlation Between Vdac1 Binding and Huvec Inhibition By Itmentioning

confidence: 95%

Antifungal drug itraconazole targets VDAC1 to modulate the AMPK/mTOR signaling axis in endothelial cells

Head

Shi

Zhao

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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Itraconazole, a clinically used antifungal drug, was found to possess potent antiangiogenic and anticancer activity that is unique among the azole antifungals. Previous mechanistic studies have shown that itraconazole inhibits the mechanistic target of rapamycin (mTOR) signaling pathway, which is known to be a critical regulator of endothelial cell function and angiogenesis. However, the molecular target of itraconazole that mediates this activity has remained unknown. Here we identify the major target of itraconazole in endothelial cells as the mitochondrial protein voltage-dependent anion channel 1 (VDAC1), which regulates mitochondrial metabolism by controlling the passage of ions and small metabolites through the outer mitochondrial membrane. VDAC1 knockdown profoundly inhibits mTOR activity and cell proliferation in human umbilical vein cells (HUVEC), uncovering a previously unknown connection between VDAC1 and mTOR. Inhibition of VDAC1 by itraconazole disrupts mitochondrial metabolism, leading to an increase in the cellular AMP:ATP ratio and activation of the AMP-activated protein kinase (AMPK), an upstream regulator of mTOR. VDAC1-knockout cells are resistant to AMPK activation and mTOR inhibition by itraconazole, demonstrating that VDAC1 is the mediator of this activity. In addition, another known VDAC-targeting compound, erastin, also activates AMPK and inhibits mTOR and proliferation in HUVEC. VDAC1 thus represents a novel upstream regulator of mTOR signaling in endothelial cells and a promising target for the development of angiogenesis inhibitors.

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Section: Correlation Between Vdac1 Binding and Huvec Inhibition By Itmentioning

confidence: 95%

Antifungal drug itraconazole targets VDAC1 to modulate the AMPK/mTOR signaling axis in endothelial cells

Head

Shi

Zhao

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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111

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“…In this study, we took a systematic top-down approach to discern the mechanism of action of AglA (Titov and Liu, 2012). Upon assessing its effects on global DNA, RNA and protein synthesis, we observed that AglA inhibited both protein and DNA synthesis without affecting RNA synthesis.…”

Section: Introductionmentioning

confidence: 99%

Inhibition of Eukaryotic Translation by the Antitumor Natural Product Agelastatin A

McClary

Zinshteyn

Meyer

et al. 2017

Cell Chemical Biology

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SUMMARY Protein synthesis plays an essential role in cell proliferation, differentiation and survival. Inhibitors of eukaryotic translation have entered the clinic, establishing the translation machinery as a promising target for chemotherapy. A recently discovered, structurally unique marine sponge-derived brominated alkaloid, (-)-agelastatin A (AglA), possesses potent antitumor activity. Its underlying mechanism of action, however, has remained unknown. Using a systematic top-down approach, we show that AglA selectively inhibits protein synthesis. Using a high-throughput chemical footprinting method, we mapped the AglA-binding site to the ribosomal A site. A 3.5-Å crystal structure of the 80S eukaryotic ribosome from S. cerevisiae in complex with AglA was obtained, revealing multiple conformational changes of the nucleotide bases in the ribosome accompanying the binding of AglA. Together, these results have unraveled the mechanism of inhibition of eukaryotic translation by AglA at atomic level, paving the way for future structural modifications to develop AglA analogs into novel anticancer agents.

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“…• Complémentation/suppression biochimique dans laquelle un extrait cellulaire est fractionné et les grâce à un ligand immobilisé sur un support ou grâce à un ligand marqué [19,20]. Différentes méthodologies (séquençage, outils immunologiques, analyse protéomique) permettent ensuite d'identifier les protéines liées à la molécule, constituant les cibles potentielles.…”

Section: Recherche De La Cible Par Des éTudes D'identification D'acteunclassified

Les criblages phénotypiques ou comment faire d’une pierre deux coups

et al. 2013

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Identification and validation of protein targets of bioactive small molecules

Cited by 37 publications

References 104 publications

Antifungal drug itraconazole targets VDAC1 to modulate the AMPK/mTOR signaling axis in endothelial cells

Antifungal drug itraconazole targets VDAC1 to modulate the AMPK/mTOR signaling axis in endothelial cells

Inhibition of Eukaryotic Translation by the Antitumor Natural Product Agelastatin A

Les criblages phénotypiques ou comment faire d’une pierre deux coups

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