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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.


Paolo Polucci, Paola Magnaghi, Mauro Angiolini, Daniela Asa, Nilla Avanzi, Alessandra Badari, Jay Bertrand, Elena Casale, Silvia Cauteruccio, Alessandra Cirla, Liviana Cozzi, Arturo Galvani, Peter K Jackson, Yichin Liu, Steven Magnuson, Beatrice Malgesini, Stefano Nuvoloni, Christian Orrenius, Federico Riccardi Sirtori, Laura Riceputi, Simona Rizzi, Beatrice Trucchi, Tom O'Brien, Antonella Isacchi, Daniele Donati, Roberto D'Alessio. Alkylsulfanyl-1,2,4-triazoles, a new class of allosteric valosine containing protein inhibitors. Synthesis and structure-activity relationships. Journal of medicinal chemistry. 2013 Jan 24;56(2):437-50

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PMID: 23245311

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