Discovery of 2-(cyclohexylmethylamino)pyrimidines as a new class of reversible valosine containing protein inhibitors.

Giovanni Cervi, Paola Magnaghi, Daniela Asa, Nilla Avanzi, Alessandra Badari, Daniela Borghi, Michele Caruso, Alessandra Cirla, Liviana Cozzi, Eduard Felder, Arturo Galvani, Fabio Gasparri, Antonio Lomolino, Steven Magnuson, Beatrice Malgesini, Ilaria Motto, Maurizio Pasi, Simona Rizzi, Barbara Salom, Graziella Sorrentino, Sonia Troiani, Barbara Valsasina, Thomas O'Brien, Antonella Isacchi, Daniele Donati, Roberto D'Alessio

Index: J. Med. Chem. 57(24) , 10443-54, (2014)

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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.