title: Discovery of 2-(cyclohexylmethylamino)pyrimidines as a new class of reversible valosine containing protein inhibitors.
abstract: Valosine-containing protein (VCP), also known as p97 or cdc48 in yeast, is a highly abundant protein belonging to the AAA ATPase family involved in a number of essential cellular functions, including ubiquitin-proteasome mediated protein degradation, Golgi reassembly, transcription activation, and cell cycle control. Altered expression of VCP has been detected in many cancer types sometimes associated with poor prognosis. Furthermore, VCP mutations are causative of some neurodegenerative disorders. In this paper we report the discovery, synthesis, and structure-activity relationships of substituted 2-aminopyrimidines, representing a new class of reversible VCP inhibitors. This class of compounds, identified in a HTS campaign against recombinant VCP, has been progressively expanded and manipulated to increase biochemical potency and gain cellular activity.
authors.affiliation: Oncology, Nerviano Medical Sciences S.r.l. , Viale Pasteur 10, 20014 Nerviano, Milan, Italy.
authors.forename: Giovanni
authors.initials: G
authors.lastname: Cervi
authors.forename: Paola
authors.initials: P
authors.lastname: Magnaghi
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: Daniela
authors.initials: D
authors.lastname: Borghi
authors.forename: Michele
authors.initials: M
authors.lastname: Caruso
authors.forename: Alessandra
authors.initials: A
authors.lastname: Cirla
authors.forename: Liviana
authors.initials: L
authors.lastname: Cozzi
authors.forename: Eduard
authors.initials: E
authors.lastname: Felder
authors.forename: Arturo
authors.initials: A
authors.lastname: Galvani
authors.forename: Fabio
authors.initials: F
authors.lastname: Gasparri
authors.forename: Antonio
authors.initials: A
authors.lastname: Lomolino
authors.forename: Steven
authors.initials: S
authors.lastname: Magnuson
authors.forename: Beatrice
authors.initials: B
authors.lastname: Malgesini
authors.forename: Ilaria
authors.initials: I
authors.lastname: Motto
authors.forename: Maurizio
authors.initials: M
authors.lastname: Pasi
authors.forename: Simona
authors.initials: S
authors.lastname: Rizzi
authors.forename: Barbara
authors.initials: B
authors.lastname: Salom
authors.forename: Graziella
authors.initials: G
authors.lastname: Sorrentino
authors.forename: Sonia
authors.initials: S
authors.lastname: Troiani
authors.forename: Barbara
authors.initials: B
authors.lastname: Valsasina
authors.forename: Thomas
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* / Q000378:metabolism; D018797:Cell Cycle Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects*; D055808:Drug Discovery; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D045325:HCT116 Cells; D006801:Humans; D008958:Models, Molecular; D015394:Molecular Structure; D011743:Pyrimidines / Q000737:chemistry* / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D000074405:Valosin Containing Protein
chemical_list: D018797:Cell Cycle Proteins; D004791:Enzyme Inhibitors; D011743:Pyrimidines; D000251:Adenosine Triphosphatases; C000614178:VCP protein, human; D000074405:Valosin Containing Protein; C030986:pyrimidine