Issue 1, 2010

Small-molecule modulators of the Sonic Hedgehog signaling pathway

Abstract

Sonic hedgehog (Shh) is the most widely characterized of the three vertebrate Hedgehoghomologs, and is essential for proper embryonic development. Shh binds to its receptor, Patched (Ptch1), resulting in the de-repression of Smoothened (Smo). This leads to the activation of Gli2, which regulates the transcription of target genes that include Gli1 and Ptch1. Several synthetic and naturally occurring small-molecule modulators of Smo have been discovered. Shh-signalingantagonists that bind to Smo include cyclopamine, SANT1, and Cur-61414. Shh signalingagonists that bind to Smo include the synthetic small molecules purmorphamine and SAG. Small molecules that inhibit Shh signalingdownstream of Smo, GANT58 and GANT61 have also been reported. Robotnikinin inhibits the Shh pathway by directly targeting Shh. Although progress has been made in understanding and modulating Shh signaling, fundamental aspects of Shh signal transduction remain obscure, including the mechanism(s) whereby Ptch1 regulates Smo activity. Small-molecule modulators of Shh signaling provide a means to regulate the activity of a pathway implicated in medulloblastoma, basal cell carcinoma (BCC), pancreatic cancer, prostate cancer and developmental disorders. Several Shh inhibitors have not succeeded in the clinic for unknown reasons, but clinical trials in BCC and pancreatic cancer with the promising Smo antagonists GDC-0449 and IPI-926 are currently underway.

Graphical abstract: Small-molecule modulators of the Sonic Hedgehog signaling pathway

Article information

Article type
Review Article
Submitted
22 May 2009
Accepted
13 Jul 2009
First published
27 Aug 2009

Mol. BioSyst., 2010,6, 44-54

Small-molecule modulators of the Sonic Hedgehog signaling pathway

B. Z. Stanton and L. F. Peng, Mol. BioSyst., 2010, 6, 44 DOI: 10.1039/B910196A

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