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Novel small molecules targeting ciliary transport of Smoothened and oncogenic Hedgehog pathway activation

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Item Type:Article
Title:Novel small molecules targeting ciliary transport of Smoothened and oncogenic Hedgehog pathway activation
Creators Name:Jung, B. and Messias, A.C. and Schorpp, K. and Geerlof, A. and Schneider, G. and Saur, D. and Hadian, K. and Sattler, M. and Wanker, E.E. and Hasenöder, S. and Lickert, H.
Abstract:Trafficking of the G protein-coupled receptor (GPCR) Smoothened (Smo) to the primary cilium (PC) is a potential target to inhibit oncogenic Hh pathway activation in a large number of tumors. One drawback is the appearance of Smo mutations that resist drug treatment, which is a common reason for cancer treatment failure. Here, we undertook a high content screen with compounds in preclinical or clinical development and identified ten small molecules that prevent constitutive active mutant SmoM2 transport into PC for subsequent Hh pathway activation. Eight of the ten small molecules act through direct interference with the G protein-coupled receptor associated sorting protein 2 (Gprasp2)-SmoM2 ciliary targeting complex, whereas one antagonist of ionotropic receptors prevents intracellular trafficking of Smo to the PC. Together, these findings identify several compounds with the potential to treat drug-resistant SmoM2-driven cancer forms, but also reveal off-target effects of established drugs in the clinics.
Keywords:Cilia, Hedgehog Proteins, Oncogenes, Pancreatic Neoplasms, Protein Transport, Signal Transduction, Smoothened Receptor, Animals, Mice
Source:Scientific Reports
ISSN:2045-2322
Publisher:Nature Publishing Group (U.K.)
Volume:6
Page Range:22540
Date:2 March 2016
Official Publication:https://doi.org/10.1038/srep22540
PubMed:View item in PubMed

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