Identification of a novel NAMPT inhibitor by CRISPR/Cas9 chemogenomic profiling in mammalian cells.

Abstract

Chemogenomic profiling is a powerful and unbiased approach to elucidate pharmacological targets and the mechanism of bioactive compounds. Until recently, genome-wide, high-resolution experiments of this nature have been limited to fungal systems due to lack of mammalian genome-wide deletion collections. With the example of a novel nicotinamide phosphoribosyltransferase (NAMPT) inhibitor, we demonstrate that the CRISPR/Cas9 system enables the generation of transient homo- and heterozygous deletion libraries and allows for the identification of efficacy targets and pathways mediating hypersensitivity and resistance relevant to the compound mechanism of action.

• Authors: David Estoppey, Jeffrey W Hewett, Chantale T Guy, Edmund Harrington, Jason R Thomas, Markus Schirle, Rachel Cuttat, Annick Waldt, Bertran Gerrits, Zinger Yang, Sven Schuierer, Xuewen Pan, Kevin Xie, Walter Carbone, Judith Knehr, Alicia Lindeman, Carsten Russ, Elizabeth Frias, Gregory R Hoffman, Malini Varadarajan, Nadire Ramadan, John S Reece-Hoyes, Qiong Wang, Xin Chen, Gregory McAllister, Guglielmo Roma, Tewis Bouwmeester, Dominic Hoepfner
• Journal: Scientific reports (Sci Rep) Vol. 7 Pg. 42728 (02 16 2017) ISSN: 2045-2322 [Electronic] England
• PMID: 28205648 (Publication Type: Journal Article)

Chemical References

• Enzyme Inhibitors
• Nicotinamide Phosphoribosyltransferase

Topics

• CRISPR-Cas Systems
• Cells, Cultured
• Drug Discovery (methods)
• Enzyme Inhibitors (chemistry, pharmacology)
• Gene Deletion
• Humans
• Induced Pluripotent Stem Cells (drug effects, metabolism)
• Nicotinamide Phosphoribosyltransferase (antagonists & inhibitors, genetics)
• Pharmacogenomic Testing (methods)