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

Daniel J Anderson; Ronan Le Moigne; Stevan Djakovic; Brajesh Kumar; Julie Rice; Steve Wong; Jinhai Wang; Bing Yao; Eduardo Valle; Szerenke Kiss von Soly; Antonett Madriaga; Ferdie Soriano; Mary-Kamala Menon; Zhi Yong Wu; Martin Kampmann; Yuwen Chen; Jonathan S Weissman; Blake T Aftab; F Michael Yakes; Laura Shawver; Han-Jie Zhou; David Wustrow; Mark Rolfe

doi:10.1016/j.ccell.2015.10.002

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

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

Authors

Daniel J Anderson¹, Ronan Le Moigne², Stevan Djakovic², Brajesh Kumar², Julie Rice², Steve Wong², Jinhai Wang², Bing Yao², Eduardo Valle², Szerenke Kiss von Soly², Antonett Madriaga², Ferdie Soriano², Mary-Kamala Menon², Zhi Yong Wu², Martin Kampmann³, Yuwen Chen³, Jonathan S Weissman³, Blake T Aftab⁴, F Michael Yakes², Laura Shawver², Han-Jie Zhou², David Wustrow², Mark Rolfe²

Affiliations

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.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Adenosine Triphosphatases / antagonists & inhibitors*
Adenosine Triphosphatases / genetics
Adenosine Triphosphatases / metabolism
Animals
Apoptosis / drug effects
Blotting, Western
CRISPR-Cas Systems
Cell Line, Tumor
Endoplasmic Reticulum-Associated Degradation / drug effects
Enzyme Inhibitors / chemistry
Enzyme Inhibitors / pharmacology*
Gene Expression Regulation, Neoplastic / drug effects
HCT116 Cells
HEK293 Cells
Homeostasis / drug effects*
Humans
Indoles / chemistry
Indoles / pharmacology
K562 Cells
Mice, Nude
Mice, SCID
Molecular Structure
Molecular Targeted Therapy / methods
Neoplasms / drug therapy*
Neoplasms / genetics
Neoplasms / metabolism
Nuclear Proteins / antagonists & inhibitors*
Nuclear Proteins / genetics
Nuclear Proteins / metabolism
Pyrimidines / chemistry
Pyrimidines / pharmacology
RNA Interference
Reverse Transcriptase Polymerase Chain Reaction
Ubiquitinated Proteins / metabolism
Xenograft Model Antitumor Assays

Substances

CB-5083
Enzyme Inhibitors
Indoles
Nuclear Proteins
Pyrimidines
Ubiquitinated Proteins
Adenosine Triphosphatases
p97 ATPase

Associated data

GEO/GSE73588

Abstract

Publication types

MeSH terms

Substances

Associated data

Grants and funding