title: Target identification for a Hedgehog pathway inhibitor reveals the receptor GPR39.
abstract: Hedgehog (Hh) signaling determines cell fate during development and can drive tumorigenesis. We performed a screen for new compounds that can impinge on Hh signaling downstream of Smoothened (Smo). A series of cyclohexyl-methyl aminopyrimidine chemotype compounds ('CMAPs') were identified that could block pathway signaling in a Smo-independent manner. In addition to inhibiting Hh signaling, the compounds generated inositol phosphates through an unknown GPCR. Correlation of GPCR mRNA expression levels with compound activity across cell lines suggested the target to be the orphan receptor GPR39. RNA interference or cDNA overexpression of GPR39 demonstrated that the receptor is necessary for compound activity. We propose a model in which CMAPs activate GPR39, which signals to the Gli transcription factors and blocks signaling. In addition to the discovery of GPR39 as a new target that impinges on Hh signaling, we report on small-molecule modulators of the receptor that will enable in vitro interrogation of GPR39 signaling in different cellular contexts.
authors.affiliation: Novartis Institutes for Biomedical Research, Basel, Switzerland.
authors.forename: Frederic
authors.identifier: 0000000320638450
authors.initials: F
authors.lastname: Bassilana
authors.affiliation: Novartis Institutes for Biomedical Research, Cambridge, Massachusetts, USA.
authors.forename: Adam
authors.initials: A
authors.lastname: Carlson
authors.affiliation: Novartis Institutes for Biomedical Research, Cambridge, Massachusetts, USA.
authors.forename: Jennifer A
authors.initials: JA
authors.lastname: DaSilva
authors.affiliation: Novartis Institutes for Biomedical Research, Basel, Switzerland.
authors.forename: Bianka
authors.initials: B
authors.lastname: Grosshans
authors.affiliation: Novartis Institutes for Biomedical Research, Basel, Switzerland.
authors.forename: Solange
authors.initials: S
authors.lastname: Vidal
authors.affiliation: Novartis Institutes for Biomedical Research, Basel, Switzerland.
authors.forename: Valerie
authors.initials: V
authors.lastname: Beck
authors.affiliation: Novartis Institutes for Biomedical Research, Basel, Switzerland.
authors.forename: Barbara
authors.initials: B
authors.lastname: Wilmeringwetter
authors.affiliation: Novartis Institutes for Biomedical Research, Cambridge, Massachusetts, USA.
authors.forename: Luis A
authors.initials: LA
authors.lastname: Llamas
authors.affiliation: Novartis Institutes for Biomedical Research, Cambridge, Massachusetts, USA.
authors.forename: Todd B
authors.initials: TB
authors.lastname: Showalter
authors.affiliation: Novartis Institutes for Biomedical Research, Basel, Switzerland.
authors.forename: Pascal
authors.initials: P
authors.lastname: Rigollier
authors.affiliation: Novartis Institutes for Biomedical Research, Cambridge, Massachusetts, USA.
authors.forename: Aaron
authors.initials: A
authors.lastname: Bourret
authors.affiliation: Novartis Institutes for Biomedical Research, Cambridge, Massachusetts, USA.
authors.forename: Arun
authors.initials: A
authors.lastname: Ramamurthy
authors.affiliation: 1] Genomics Institute of the Novartis Research Foundation, San Diego, California, USA. [2].
authors.forename: Xu
authors.initials: X
authors.lastname: Wu
authors.affiliation: Novartis Institutes for Biomedical Research, Cambridge, Massachusetts, USA.
authors.forename: Fred
authors.initials: F
authors.lastname: Harbinski
authors.affiliation: Novartis Institutes for Biomedical Research, Cambridge, Massachusetts, USA.
authors.forename: Samantha
authors.initials: S
authors.lastname: Plonsky
authors.affiliation: Novartis Institutes for Biomedical Research, Cambridge, Massachusetts, USA.
authors.forename: Lac
authors.initials: L
authors.lastname: Lee
authors.affiliation: 1] Cellzome AG, Heidelberg, Germany. [2].
authors.forename: Heinz
authors.initials: H
authors.lastname: Ruffner
authors.affiliation: Cellzome AG, Heidelberg, Germany.
authors.forename: Paola
authors.initials: P
authors.lastname: Grandi
authors.affiliation: 1] Cellzome AG, Heidelberg, Germany. [2].
authors.forename: Markus
authors.initials: M
authors.lastname: Schirle
authors.affiliation: Novartis Institutes for Biomedical Research, Cambridge, Massachusetts, USA.
authors.forename: Jeremy
authors.initials: J
authors.lastname: Jenkins
authors.affiliation: Novartis Institutes for Biomedical Research, Basel, Switzerland.
authors.forename: Andreas W
authors.initials: AW
authors.lastname: Sailer
authors.affiliation: 1] Cellzome AG, Heidelberg, Germany. [2].
authors.forename: Tewis
authors.initials: T
authors.lastname: Bouwmeester
authors.affiliation: Novartis Institutes for Biomedical Research, Cambridge, Massachusetts, USA.
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: Porter
authors.affiliation: Novartis Institutes for Biomedical Research, Cambridge, Massachusetts, USA.
authors.forename: Vic
authors.initials: V
authors.lastname: Myer
authors.affiliation: 1] Novartis Institutes for Biomedical Research, Cambridge, Massachusetts, USA. [2].
authors.forename: Peter M
authors.initials: PM
authors.lastname: Finan
authors.affiliation: Novartis Institutes for Biomedical Research, Cambridge, Massachusetts, USA.
authors.forename: John A
authors.initials: JA
authors.lastname: Tallarico
authors.affiliation: Novartis Institutes for Biomedical Research, Cambridge, Massachusetts, USA.
authors.forename: Joseph F
authors.initials: JF
authors.lastname: Kelleher
authors.affiliation: Novartis Institutes for Biomedical Research, Basel, Switzerland.
authors.forename: Klaus
authors.initials: K
authors.lastname: Seuwen
authors.affiliation: Novartis Institutes for Biomedical Research, Cambridge, Massachusetts, USA.
authors.forename: Rishi K
authors.initials: RK
authors.lastname: Jain
authors.affiliation: Novartis Institutes for Biomedical Research, Cambridge, Massachusetts, USA.
authors.forename: Sarah J
authors.initials: SJ
authors.lastname: Luchansky
mesh_terms: D002846:Chromatography, Affinity; D053823:Hedgehog Proteins / Q000037:antagonists & inhibitors*; D040901:Proteomics; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism*; D015398:Signal Transduction; D053719:Tandem Mass Spectrometry
chemical_list: C495797:GPR39 protein, human; D053823:Hedgehog Proteins; D043562:Receptors, G-Protein-Coupled