title: 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.affiliation: Novartis Institutes for BioMedical Research, Novartis Pharma AG, Forum 1 Novartis Campus, CH-4056 Basel, Switzerland.
authors.forename: David
authors.initials: D
authors.lastname: Estoppey
authors.affiliation: Novartis Institutes for BioMedical Research, 250 Massachusetts Avenue, Cambridge, MA 02139, USA.
authors.forename: Jeffrey W
authors.initials: JW
authors.lastname: Hewett
authors.affiliation: Novartis Institutes for BioMedical Research, 250 Massachusetts Avenue, Cambridge, MA 02139, USA.
authors.forename: Chantale T
authors.initials: CT
authors.lastname: Guy
authors.affiliation: Novartis Institutes for BioMedical Research, 250 Massachusetts Avenue, Cambridge, MA 02139, USA.
authors.forename: Edmund
authors.initials: E
authors.lastname: Harrington
authors.affiliation: Novartis Institutes for BioMedical Research, 250 Massachusetts Avenue, Cambridge, MA 02139, USA.
authors.forename: Jason R
authors.initials: JR
authors.lastname: Thomas
authors.affiliation: Novartis Institutes for BioMedical Research, 250 Massachusetts Avenue, Cambridge, MA 02139, USA.
authors.forename: Markus
authors.initials: M
authors.lastname: Schirle
authors.affiliation: Novartis Institutes for BioMedical Research, Novartis Pharma AG, Forum 1 Novartis Campus, CH-4056 Basel, Switzerland.
authors.forename: Rachel
authors.initials: R
authors.lastname: Cuttat
authors.affiliation: Novartis Institutes for BioMedical Research, Novartis Pharma AG, Forum 1 Novartis Campus, CH-4056 Basel, Switzerland.
authors.forename: Annick
authors.initials: A
authors.lastname: Waldt
authors.affiliation: Novartis Institutes for BioMedical Research, Novartis Pharma AG, Forum 1 Novartis Campus, CH-4056 Basel, Switzerland.
authors.forename: Bertran
authors.initials: B
authors.lastname: Gerrits
authors.affiliation: Novartis Institutes for BioMedical Research, 250 Massachusetts Avenue, Cambridge, MA 02139, USA.
authors.forename: Zinger
authors.initials: Z
authors.lastname: Yang
authors.affiliation: Novartis Institutes for BioMedical Research, Novartis Pharma AG, Forum 1 Novartis Campus, CH-4056 Basel, Switzerland.
authors.forename: Sven
authors.initials: S
authors.lastname: Schuierer
authors.affiliation: Novartis Institutes for BioMedical Research, 250 Massachusetts Avenue, Cambridge, MA 02139, USA.
authors.forename: Xuewen
authors.initials: X
authors.lastname: Pan
authors.affiliation: Novartis Institutes for BioMedical Research, 250 Massachusetts Avenue, Cambridge, MA 02139, USA.
authors.forename: Kevin
authors.initials: K
authors.lastname: Xie
authors.affiliation: Novartis Institutes for BioMedical Research, Novartis Pharma AG, Forum 1 Novartis Campus, CH-4056 Basel, Switzerland.
authors.forename: Walter
authors.initials: W
authors.lastname: Carbone
authors.affiliation: Novartis Institutes for BioMedical Research, Novartis Pharma AG, Forum 1 Novartis Campus, CH-4056 Basel, Switzerland.
authors.forename: Judith
authors.initials: J
authors.lastname: Knehr
authors.affiliation: Novartis Institutes for BioMedical Research, 250 Massachusetts Avenue, Cambridge, MA 02139, USA.
authors.forename: Alicia
authors.initials: A
authors.lastname: Lindeman
authors.affiliation: Novartis Institutes for BioMedical Research, 250 Massachusetts Avenue, Cambridge, MA 02139, USA.
authors.forename: Carsten
authors.initials: C
authors.lastname: Russ
authors.affiliation: Novartis Institutes for BioMedical Research, 250 Massachusetts Avenue, Cambridge, MA 02139, USA.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Frias
authors.affiliation: Novartis Institutes for BioMedical Research, 250 Massachusetts Avenue, Cambridge, MA 02139, USA.
authors.forename: Gregory R
authors.initials: GR
authors.lastname: Hoffman
authors.affiliation: Novartis Institutes for BioMedical Research, 250 Massachusetts Avenue, Cambridge, MA 02139, USA.
authors.forename: Malini
authors.initials: M
authors.lastname: Varadarajan
authors.affiliation: Novartis Institutes for BioMedical Research, 250 Massachusetts Avenue, Cambridge, MA 02139, USA.
authors.forename: Nadire
authors.initials: N
authors.lastname: Ramadan
authors.affiliation: Novartis Institutes for BioMedical Research, 250 Massachusetts Avenue, Cambridge, MA 02139, USA.
authors.forename: John S
authors.initials: JS
authors.lastname: Reece-Hoyes
authors.affiliation: Novartis Institutes for BioMedical Research, 250 Massachusetts Avenue, Cambridge, MA 02139, USA.
authors.forename: Qiong
authors.initials: Q
authors.lastname: Wang
authors.affiliation: Novartis Institutes for BioMedical Research, 250 Massachusetts Avenue, Cambridge, MA 02139, USA.
authors.forename: Xin
authors.initials: X
authors.lastname: Chen
authors.affiliation: Novartis Institutes for BioMedical Research, 250 Massachusetts Avenue, Cambridge, MA 02139, USA.
authors.forename: Gregory
authors.initials: G
authors.lastname: McAllister
authors.affiliation: Novartis Institutes for BioMedical Research, Novartis Pharma AG, Forum 1 Novartis Campus, CH-4056 Basel, Switzerland.
authors.forename: Guglielmo
authors.initials: G
authors.lastname: Roma
authors.affiliation: Novartis Institutes for BioMedical Research, Novartis Pharma AG, Forum 1 Novartis Campus, CH-4056 Basel, Switzerland.
authors.forename: Tewis
authors.initials: T
authors.lastname: Bouwmeester
authors.affiliation: Novartis Institutes for BioMedical Research, Novartis Pharma AG, Forum 1 Novartis Campus, CH-4056 Basel, Switzerland.
authors.forename: Dominic
authors.initials: D
authors.lastname: Hoepfner
mesh_terms: D064113:CRISPR-Cas Systems; D002478:Cells, Cultured; D055808:Drug Discovery / Q000379:methods*; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D017353:Gene Deletion; D006801:Humans; D057026:Induced Pluripotent Stem Cells / Q000187:drug effects / Q000378:metabolism; D054409:Nicotinamide Phosphoribosyltransferase / Q000037:antagonists & inhibitors* / Q000235:genetics; D000071185:Pharmacogenomic Testing / Q000379:methods
chemical_list: D004791:Enzyme Inhibitors; D054409:Nicotinamide Phosphoribosyltransferase