P97 is an important cellular AAA ATPase also known as VCP (Valosin Containing Protein) that has a well described role as a master regulator in the Ubiquitin Proteasome System. P97/VCP extracts misfolded proteins from membranes, such as the endoplasmic reticulum, and chaperones them to the proteasome for degradation.1 Emerging evidence suggests that cancer cells become over-dependent on protein homeostasis systems and therefore inhibitors of p97 are expected to have meaningful anti-cancer activity.2 Genetic knockdown of p97 leads to cell death in a number of solid tumor cell lines and compounds that inhibit p97 have been discovered which lead to cancer cell death in various pre-clinical models.3, 4

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  1. Meyer H, Bug M, Bremer S (2012) Emerging functions of the VCP/p97 AAA-ATPase in the ubiquitin system. Nature Cell Biology 14: 117-123
  2. Cenci S, Oliva L, Cerruti F, Milan E, Bianchi G, Raule M, Mezghrani A, Pasqualetto E, Sitia R and Cascio P (2012) Protein synthesis modulates responsiveness of differentiating and malignant plasma cells to proteasome inhibitors. Journal of Leukocyte Biology 92: 921-931
  3. Magnaghi P, D'Alessio R, Valsasina B, Avanzi N, Rizzi S, Asa D, Gasparri F, Cozzi L, Cucchi U, Orrenius C, Polucci P, Ballinari D, Perrera C, Leone A, Cervi G, Casale E, Xiao Y, Wong C, Anderson DJ, Galvani A, Donati D, O'Brien T, Jackson PK and Isacchi A (2013) Covalent and allosteric inhibitors of the ATPase VCP/p97 induce cancer cell death. Nature Chemical Biology 9: 548-556
  4. Djakovic SN, Anderson DJ, Kiss von Soly S, Le Moigne R, Rice J, Rolfe M, Soriano F, Valle E, Wang J, Wong S, Wustrow D, Yakes FM, Yao B, Zhou H (2013) Novel small molecule inhibitors of p97 disrupt cellular protein homeostasis and demonstrate anti-tumor activity in solid and hematological models. Poster presented at: Proceedings of the 2013 AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; Boston, Massachusetts