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Jung, B. ; Messias, A.C. ; Schorpp, K.K. ; Geerlof, A. ; Schneider, G.* ; Saur, D.* ; Hadian, K. ; Sattler, M. ; Wanker, E.E.* ; Hasenöder, S. ; Lickert, H.

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

Sci. Rep. 6:22540 (2016)
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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.
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Publication type Article: Journal article
Document type Scientific Article
Keywords Pancreatic Ductal Adenocarcinoma; Basal-cell Carcinoma; Protein-kinase-c; Signaling Pathway; Primary Cilium; Combination Chemotherapy; Acinar-cells; Solid Tumors; Mouse Model; In-vivo
ISSN (print) / ISBN 2045-2322
e-ISSN 2045-2322
Quellenangaben Volume: 6, Issue: , Pages: , Article Number: 22540 Supplement: ,
Publisher Nature Publishing Group
Publishing Place London
Reviewing status Peer reviewed