Small-molecule agonists of GPR39, an orphan GPCR, are SMO-independent Hedgehog pathway inhibitors.

  • Major finding: Small-molecule agonists of GPR39, an orphan GPCR, are SMO-independent Hedgehog pathway inhibitors.

  • Mechanism: GPR39 activates IP3-mediated second messenger signaling to activate MAPK signaling and inhibit GLI1/2.

  • Impact: GPR39 is a potential therapeutic target in SMO inhibitor-resistant Hedgehog-driven tumors.

The Hedgehog signaling cascade is a key regulator of cell fate during development and is aberrantly activated in human cancers. Inhibitors of Smoothened (SMO), a G protein-coupled receptor (GPCR)–like mediator of Hedgehog signaling, have therapeutic potential in Hedgehog pathway–driven cancers, but acquired resistance can arise through reactivation of the downstream GLI transcription factors. To identify SMO-independent Hedgehog pathway inhibitors, Bassilana and colleagues performed a high-throughput cell-based reporter screen of a large compound library and found that cyclohexyl-methyl aminopyrimidines (CMAP) suppressed GLI-driven luciferase cassette expression in the presence of a SMO agonist or GLI1 overexpression and reduced expression of Hedgehog pathway target genes independently of SMO binding. Identification of the target(s) of the CMAP compounds focused on GPCRs, as membrane permeability was not essential for CMAP activity and the CMAP scaffold resembled previously characterized GPCR antagonists. However, CMAP treatment stimulated production of the second messenger inositol triphosphate (IP3), an indicator of GPCR activation. GPCR mRNA profiling in human and murine cell lines revealed a candidate target, G protein-coupled receptor 39 (GPR39), which was highly expressed in CMAP-responsive cell types. Overexpression of GPR39 sensitized nonresponsive cells to CMAP treatment, with GPR39 activation stimulating IP3 production and reducing GLI1/2 activity in a MAPK pathway–dependent manner. Moreover, GPR39 depletion reduced CMAP potency without affecting SMO inhibitor activity. The identification of CMAPs as SMO-independent inhibitors of Hedgehog signaling that act as GPR39 agonists implicates the orphan receptor GPR39 as a modulator of the Hedgehog pathway and suggests that GRP39 may represent a potential therapeutic target for Hedgehog pathway–driven tumors, including those with acquired SMO inhibitor resistance.

Bassilana F, Carlson A, DaSilva JA, Grosshans B, Vidal S, Beck V, et al. Target identification for a Hedgehog pathway inhibitor reveals the receptor GPR39. Nat Chem Biol 2014 Mar 16 [Epub ahead of print].

Note:Research Watch is written by Cancer Discovery Science Writers. Readers are encouraged to consult the original articles for full details. For more Research Watch, visit Cancer Discovery online at