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Target identification for a Hedgehog pathway inhibitor reveals the receptor GPR39

Bassilana, Frederic, Carlson, Adam, Dasilva, Jennifer, Grosshans, Bianka, Vidal, Solange, Beck, Valerie, Wilmering Wetter, Barbara, Llamas, Luis, Bourret, Aaron, Wu, Xu, Harbinski, Fred, Ruffner, Heinz, Grandi, Paola, Schirle, Markus, Jenkins, Jeremy, Bouwmeester, Antonius, Porter, Jeffrey, Myer, Vic, Finan, Peter, Tallarico, John, Kelleher Iii, Joseph, Seuwen, Klaus, Jain, Rishi and Luchansky, Sarah (2014) Target identification for a Hedgehog pathway inhibitor reveals the receptor GPR39. Nature Chemical Biology, 10 (5). pp. 343-349. ISSN 1552-4469


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.© 2014 Nature America, Inc. All rights reserved.

Item Type: Article
Date Deposited: 25 Nov 2017 00:45
Last Modified: 25 Jan 2019 00:46


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