title: Novel small molecules targeting ciliary transport of Smoothened and oncogenic Hedgehog pathway activation.
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.
authors.affiliation: Institute of Diabetes and Regeneration Research, Helmholtz Zentrum München, Germany.|Institute of Stem Cell Research, Helmholtz Zentrum München, Germany.
authors.forename: Bomi
authors.initials: B
authors.lastname: Jung
authors.affiliation: Institute of Structural Biology, Helmholtz Zentrum München, Germany.|Center for Integrated Protein Science Munich at Biomolecular NMR Spectroscopy, Department Chemistry, Technische Universität München, 85747 Garching, Germany.
authors.forename: Ana C
authors.initials: AC
authors.lastname: Messias
authors.affiliation: Assay Development and Screening Platform, Helmholtz Zentrum München, Germany.
authors.forename: Kenji
authors.initials: K
authors.lastname: Schorpp
authors.affiliation: Institute of Structural Biology, Helmholtz Zentrum München, Germany.
authors.forename: Arie
authors.initials: A
authors.lastname: Geerlof
authors.affiliation: Department of Internal Medicine II, Klinikum rechts der Isar, München, Germany.|Technische Universität München, München, Germany.
authors.forename: Günter
authors.initials: G
authors.lastname: Schneider
authors.affiliation: Department of Internal Medicine II, Klinikum rechts der Isar, München, Germany.|Technische Universität München, München, Germany.|German Cancer Consortium (DKTK), Heidelberg, Germany.|German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: Dieter
authors.initials: D
authors.lastname: Saur
authors.affiliation: Assay Development and Screening Platform, Helmholtz Zentrum München, Germany.
authors.forename: Kamyar
authors.initials: K
authors.lastname: Hadian
authors.affiliation: Institute of Structural Biology, Helmholtz Zentrum München, Germany.|Center for Integrated Protein Science Munich at Biomolecular NMR Spectroscopy, Department Chemistry, Technische Universität München, 85747 Garching, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Sattler
authors.affiliation: Neuroproteomics, Max Delbrueck Center for Molecular Medicine, 13125 Berlin, Germany.
authors.forename: Erich E
authors.initials: EE
authors.lastname: Wanker
authors.affiliation: Institute of Diabetes and Regeneration Research, Helmholtz Zentrum München, Germany.|Institute of Stem Cell Research, Helmholtz Zentrum München, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Hasenöder
authors.affiliation: Institute of Diabetes and Regeneration Research, Helmholtz Zentrum München, Germany.|Institute of Stem Cell Research, Helmholtz Zentrum München, Germany.|Technische Universität München, München, Germany.|German Center for Diabetes Research (DZD), Germany.
authors.forename: Heiko
authors.initials: H
authors.lastname: Lickert
mesh_terms: D000818:Animals; D002923:Cilia / Q000378:metabolism*; D053823:Hedgehog Proteins / Q000378:metabolism*; D051379:Mice; D009857:Oncogenes; D010190:Pancreatic Neoplasms / Q000378:metabolism; D021381:Protein Transport; D015398:Signal Transduction; D000072086:Smoothened Receptor / Q000378:metabolism*
chemical_list: D053823:Hedgehog Proteins; C491022:Smo protein, mouse; D000072086:Smoothened Receptor