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

  • Sci Rep. 2017 Feb 16;7:42728. doi: 10.1038/srep42728.
David Estoppey  1 ,  Jeffrey W Hewett  2 ,  Chantale T Guy  2 ,  Edmund Harrington  2 ,  Jason R Thomas  2 ,  Markus Schirle  2 ,  Rachel Cuttat  1 ,  Annick Waldt  1 ,  Bertran Gerrits  1 ,  Zinger Yang  2 ,  Sven Schuierer  1 ,  Xuewen Pan  2 ,  Kevin Xie  2 ,  Walter Carbone  1 ,  Judith Knehr  1 ,  Alicia Lindeman  2 ,  Carsten Russ  2 ,  Elizabeth Frias  2 ,  Gregory R Hoffman  2 ,  Malini Varadarajan  2 ,  Nadire Ramadan  2 ,  John S Reece-Hoyes  2 ,  Qiong Wang  2 ,  Xin Chen  2 ,  Gregory McAllister  2 ,  Guglielmo Roma  1 ,  Tewis Bouwmeester  1 ,  Dominic Hoepfner  1
Affiliations
  • 1. Novartis Institutes for BioMedical Research, Novartis Pharma AG, Forum 1 Novartis Campus, CH-4056 Basel, Switzerland.
  • 2. Novartis Institutes for BioMedical Research, 250 Massachusetts Avenue, Cambridge, MA 02139, USA.
PMID: 28205648 DOI: 10.1038/srep42728
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.

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