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Ref Type Journal Article
PMID (27694802)
Authors Lopez-Sambrooks C, Shrimal S, Khodier C, Flaherty DP, Rinis N, Charest JC, Gao N, Zhao P, Wells L, Lewis TA, Lehrman MA, Gilmore R, Golden JE, Contessa JN
Title Oligosaccharyltransferase inhibition induces senescence in RTK-driven tumor cells.
Journal Nature chemical biology
Vol 12
Issue 12
Date 2016 Dec
URL
Abstract Text Asparagine (N)-linked glycosylation is a protein modification critical for glycoprotein folding, stability, and cellular localization. To identify small molecules that inhibit new targets in this biosynthetic pathway, we initiated a cell-based high-throughput screen and lead-compound-optimization campaign that delivered a cell-permeable inhibitor, NGI-1. NGI-1 targets oligosaccharyltransferase (OST), a hetero-oligomeric enzyme that exists in multiple isoforms and transfers oligosaccharides to recipient proteins. In non-small-cell lung cancer cells, NGI-1 blocks cell-surface localization and signaling of the epidermal growth factor receptor (EGFR) glycoprotein, but selectively arrests proliferation in only those cell lines that are dependent on EGFR (or fibroblast growth factor, FGFR) for survival. In these cell lines, OST inhibition causes cell-cycle arrest accompanied by induction of p21, autofluorescence, and cell morphology changes, all hallmarks of senescence. These results identify OST inhibition as a potential therapeutic approach for treating receptor-tyrosine-kinase-dependent tumors and provides a chemical probe for reversibly regulating N-linked glycosylation in mammalian cells.

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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
NGI-1 NGI-1 1 0
Drug Name Trade Name Synonyms Drug Classes Drug Description
NGI-1 ML414 NGI-1 inhibits the activity of oligosacchyltransferase, which results in reduced N-linked glycosylation and may lead to decreased proliferation of tumor cells with dependence on receptor tyrosine kinase signaling (PMID: 27694802, PMID: 31511384).
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
FGFR1 amp lung non-small cell carcinoma predicted - sensitive NGI-1 Preclinical - Cell culture Actionable In a preclinical study, NGI-1 inhibited FGFR1 phosphorylation and proliferation of a FGFR1-amplified cell line dependent on FGFR1 signaling in culture, however, did not inhibit proliferation of an FGFR1-amplified cell line not dependent on FGFR1 signaling (PMID: 27694802). 27694802