title: Acylthiourea, acylurea, and acylguanidine derivatives with potent hedgehog inhibiting activity.
abstract: The Smoothened (Smo) receptor is the major transducer of the Hedgehog (Hh) signaling pathway. On the basis of the structure of the acylthiourea Smo antagonist (MRT-10), a number of different series of analogous compounds were prepared by ligand-based structural optimization. The acylthioureas, originally identified as actives, were converted into the corresponding acylureas or acylguanidines. In each series, similar structural trends delivered potent compounds with IC(50) values in the nanomolar range with respect to the inhibition of the Hh signaling pathway in various cell-based assays and of BODIPY-cyclopamine binding to human Smo. The similarity of their biological activities, in spite of discrete structural differences, may reveal the existence of hydrogen-bonding interactions between the ligands and the receptor pocket. Biological potency of compounds 61, 72, and 86 (MRT-83) were comparable to those of the clinical candidate GDC-0449. These findings suggest that these original molecules will help delineate Smo and Hh functions and can be developed as potential anticancer agents.
authors.affiliation: Dipartimento Farmaco Chimico Tecnologico, Università degli Studi di Siena, Via A. Moro 2, I-53100 Siena, Italy.
authors.forename: Antonio
authors.initials: A
authors.lastname: Solinas
authors.forename: Hélène
authors.initials: H
authors.lastname: Faure
authors.forename: Hermine
authors.initials: H
authors.lastname: Roudaut
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Traiffort
authors.forename: Angèle
authors.initials: A
authors.lastname: Schoenfelder
authors.forename: André
authors.initials: A
authors.lastname: Mann
authors.forename: Fabrizio
authors.initials: F
authors.lastname: Manetti
authors.forename: Maurizio
authors.initials: M
authors.lastname: Taddei
authors.forename: Martial
authors.initials: M
authors.lastname: Ruat
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D002454:Cell Differentiation / Q000187:drug effects; D002478:Cells, Cultured; D002531:Cerebellum / Q000166:cytology; D006146:Guanidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D053823:Hedgehog Proteins / Q000037:antagonists & inhibitors*; D006801:Humans; D006860:Hydrogen Bonding; D059630:Mesenchymal Stem Cells / Q000166:cytology / Q000187:drug effects; D051379:Mice; D008958:Models, Molecular; D010006:Osteoblasts / Q000166:cytology / Q000187:drug effects; D039904:Pluripotent Stem Cells / Q000166:cytology / Q000187:drug effects; D051381:Rats; D043562:Receptors, G-Protein-Coupled / Q000037:antagonists & inhibitors*; D015398:Signal Transduction; D000072086:Smoothened Receptor; D013329:Structure-Activity Relationship; D013890:Thiourea / Q000031:analogs & derivatives / Q000737:chemistry / Q000494:pharmacology; D014508:Urea / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000494:pharmacology
chemical_list: D000970:Antineoplastic Agents; D006146:Guanidines; D053823:Hedgehog Proteins; D043562:Receptors, G-Protein-Coupled; C509239:SHH protein, human; C491023:SMO protein, human; D000072086:Smoothened Receptor; D014508:Urea; D013890:Thiourea