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Cancer Cell. 2015 Nov 9;28(5):653-665. doi: 10.1016/j.ccell.2015.10.002.

Targeting the AAA ATPase p97 as an Approach to Treat Cancer through Disruption of Protein Homeostasis.

Author information

1
Cleave Biosciences, Inc., Burlingame, CA 94010, USA. Electronic address: danderson@cleavebio.com.
2
Cleave Biosciences, Inc., Burlingame, CA 94010, USA.
3
Department of Cellular and Molecular Pharmacology and Howard Hughes Medical Institute, University of California, San Francisco, San Francisco, CA 94158, USA.
4
Division of Hematology & Oncology, Department of Medicine, Helen Diller Family Cancer Center, University of California, San Francisco, San Francisco, CA 94158, USA.

Abstract

p97 is a AAA-ATPase with multiple cellular functions, one of which is critical regulation of protein homeostasis pathways. We describe the characterization of CB-5083, a potent, selective, and orally bioavailable inhibitor of p97. Treatment of tumor cells with CB-5083 leads to accumulation of poly-ubiquitinated proteins, retention of endoplasmic reticulum-associated degradation (ERAD) substrates, and generation of irresolvable proteotoxic stress, leading to activation of the apoptotic arm of the unfolded protein response. In xenograft models, CB-5083 causes modulation of key p97-related pathways, induces apoptosis, and has antitumor activity in a broad range of both hematological and solid tumor models. Molecular determinants of CB-5083 activity include expression of genes in the ERAD pathway, providing a potential strategy for patient selection.

PMID:
26555175
PMCID:
PMC4941640
DOI:
10.1016/j.ccell.2015.10.002
[Indexed for MEDLINE]
Free PMC Article

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