title: Alkylsulfanyl-1,2,4-triazoles, a new class of allosteric valosine containing protein inhibitors. Synthesis and structure-activity relationships.
abstract: Valosine containing protein (VCP), also known as p97, is a member of AAA ATPase family that is involved in several biological processes and plays a central role in the ubiquitin-mediated degradation of misfolded proteins. VCP is an ubiquitously expressed, highly abundant protein and has been found overexpressed in many tumor types, sometimes associated with poor prognosis. In this respect, VCP has recently received a great deal of attention as a potential new target for cancer therapy. In this paper, the discovery and structure-activity relationships of alkylsulfanyl-1,2,4-triazoles, a new class of potent, allosteric VCP inhibitors, are described. Medicinal chemistry manipulation of compound 1, identified via HTS, led to the discovery of potent and selective inhibitors with submicromolar activity in cells and clear mechanism of action at consistent doses. This represents a first step toward a new class of potential anticancer agents.
authors.affiliation: Nerviano Medical Sciences S.r.l., Oncology, Viale Pasteur 10, 20014 Nerviano (MI), Italy.
authors.forename: Paolo
authors.initials: P
authors.lastname: Polucci
authors.forename: Paola
authors.initials: P
authors.lastname: Magnaghi
authors.forename: Mauro
authors.initials: M
authors.lastname: Angiolini
authors.forename: Daniela
authors.initials: D
authors.lastname: Asa
authors.forename: Nilla
authors.initials: N
authors.lastname: Avanzi
authors.forename: Alessandra
authors.initials: A
authors.lastname: Badari
authors.forename: Jay
authors.initials: J
authors.lastname: Bertrand
authors.forename: Elena
authors.initials: E
authors.lastname: Casale
authors.forename: Silvia
authors.initials: S
authors.lastname: Cauteruccio
authors.forename: Alessandra
authors.initials: A
authors.lastname: Cirla
authors.forename: Liviana
authors.initials: L
authors.lastname: Cozzi
authors.forename: Arturo
authors.initials: A
authors.lastname: Galvani
authors.forename: Peter K
authors.initials: PK
authors.lastname: Jackson
authors.forename: Yichin
authors.initials: Y
authors.lastname: Liu
authors.forename: Steven
authors.initials: S
authors.lastname: Magnuson
authors.forename: Beatrice
authors.initials: B
authors.lastname: Malgesini
authors.forename: Stefano
authors.initials: S
authors.lastname: Nuvoloni
authors.forename: Christian
authors.initials: C
authors.lastname: Orrenius
authors.forename: Federico Riccardi
authors.initials: FR
authors.lastname: Sirtori
authors.forename: Laura
authors.initials: L
authors.lastname: Riceputi
authors.forename: Simona
authors.initials: S
authors.lastname: Rizzi
authors.forename: Beatrice
authors.initials: B
authors.lastname: Trucchi
authors.forename: Tom
authors.initials: T
authors.lastname: O'Brien
authors.forename: Antonella
authors.initials: A
authors.lastname: Isacchi
authors.forename: Daniele
authors.initials: D
authors.lastname: Donati
authors.forename: Roberto
authors.initials: R
authors.lastname: D'Alessio
mesh_terms: D000251:Adenosine Triphosphatases / Q000037:antagonists & inhibitors* / Q000737:chemistry; D000494:Allosteric Regulation; D018797:Cell Cycle Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry; D006801:Humans; D009369:Neoplasms / Q000473:pathology; D013329:Structure-Activity Relationship; D014230:Triazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D000074405:Valosin Containing Protein
chemical_list: D018797:Cell Cycle Proteins; D014230:Triazoles; D000251:Adenosine Triphosphatases; C000614178:VCP protein, human; D000074405:Valosin Containing Protein