title: Targeting the AAA ATPase p97 as an Approach to Treat Cancer through Disruption of Protein Homeostasis.
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.
authors.affiliation: Cleave Biosciences, Inc., Burlingame, CA 94010, USA. Electronic address: danderson@cleavebio.com.
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Anderson
authors.affiliation: Cleave Biosciences, Inc., Burlingame, CA 94010, USA.
authors.forename: Ronan
authors.initials: R
authors.lastname: Le Moigne
authors.affiliation: Cleave Biosciences, Inc., Burlingame, CA 94010, USA.
authors.forename: Stevan
authors.initials: S
authors.lastname: Djakovic
authors.affiliation: Cleave Biosciences, Inc., Burlingame, CA 94010, USA.
authors.forename: Brajesh
authors.initials: B
authors.lastname: Kumar
authors.affiliation: Cleave Biosciences, Inc., Burlingame, CA 94010, USA.
authors.forename: Julie
authors.initials: J
authors.lastname: Rice
authors.affiliation: Cleave Biosciences, Inc., Burlingame, CA 94010, USA.
authors.forename: Steve
authors.initials: S
authors.lastname: Wong
authors.affiliation: Cleave Biosciences, Inc., Burlingame, CA 94010, USA.
authors.forename: Jinhai
authors.initials: J
authors.lastname: Wang
authors.affiliation: Cleave Biosciences, Inc., Burlingame, CA 94010, USA.
authors.forename: Bing
authors.initials: B
authors.lastname: Yao
authors.affiliation: Cleave Biosciences, Inc., Burlingame, CA 94010, USA.
authors.forename: Eduardo
authors.initials: E
authors.lastname: Valle
authors.affiliation: Cleave Biosciences, Inc., Burlingame, CA 94010, USA.
authors.forename: Szerenke
authors.initials: S
authors.lastname: Kiss von Soly
authors.affiliation: Cleave Biosciences, Inc., Burlingame, CA 94010, USA.
authors.forename: Antonett
authors.initials: A
authors.lastname: Madriaga
authors.affiliation: Cleave Biosciences, Inc., Burlingame, CA 94010, USA.
authors.forename: Ferdie
authors.initials: F
authors.lastname: Soriano
authors.affiliation: Cleave Biosciences, Inc., Burlingame, CA 94010, USA.
authors.forename: Mary-Kamala
authors.initials: MK
authors.lastname: Menon
authors.affiliation: Cleave Biosciences, Inc., Burlingame, CA 94010, USA.
authors.forename: Zhi Yong
authors.initials: ZY
authors.lastname: Wu
authors.affiliation: Department of Cellular and Molecular Pharmacology and Howard Hughes Medical Institute, University of California, San Francisco, San Francisco, CA 94158, USA.
authors.forename: Martin
authors.initials: M
authors.lastname: Kampmann
authors.affiliation: Department of Cellular and Molecular Pharmacology and Howard Hughes Medical Institute, University of California, San Francisco, San Francisco, CA 94158, USA.
authors.forename: Yuwen
authors.initials: Y
authors.lastname: Chen
authors.affiliation: Department of Cellular and Molecular Pharmacology and Howard Hughes Medical Institute, University of California, San Francisco, San Francisco, CA 94158, USA.
authors.forename: Jonathan S
authors.initials: JS
authors.lastname: Weissman
authors.affiliation: Division of Hematology & Oncology, Department of Medicine, Helen Diller Family Cancer Center, University of California, San Francisco, San Francisco, CA 94158, USA.
authors.forename: Blake T
authors.initials: BT
authors.lastname: Aftab
authors.affiliation: Cleave Biosciences, Inc., Burlingame, CA 94010, USA.
authors.forename: F Michael
authors.initials: FM
authors.lastname: Yakes
authors.affiliation: Cleave Biosciences, Inc., Burlingame, CA 94010, USA.
authors.forename: Laura
authors.initials: L
authors.lastname: Shawver
authors.affiliation: Cleave Biosciences, Inc., Burlingame, CA 94010, USA.
authors.forename: Han-Jie
authors.initials: HJ
authors.lastname: Zhou
authors.affiliation: Cleave Biosciences, Inc., Burlingame, CA 94010, USA.
authors.forename: David
authors.initials: D
authors.lastname: Wustrow
authors.affiliation: Cleave Biosciences, Inc., Burlingame, CA 94010, USA.
authors.forename: Mark
authors.initials: M
authors.lastname: Rolfe
mesh_terms: D000251:Adenosine Triphosphatases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D064113:CRISPR-Cas Systems; D045744:Cell Line, Tumor; D060746:Endoplasmic Reticulum-Associated Degradation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D045325:HCT116 Cells; D057809:HEK293 Cells; D006706:Homeostasis / Q000187:drug effects*; D006801:Humans; D007211:Indoles / Q000737:chemistry / Q000494:pharmacology; D020014:K562 Cells; D008819:Mice, Nude; D016513:Mice, SCID; D015394:Molecular Structure; D058990:Molecular Targeted Therapy / Q000379:methods; D009369:Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D009687:Nuclear Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D011743:Pyrimidines / Q000737:chemistry / Q000494:pharmacology; D034622:RNA Interference; D020133:Reverse Transcriptase Polymerase Chain Reaction; D057149:Ubiquitinated Proteins / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
chemical_list: C000606272:CB-5083; D004791:Enzyme Inhibitors; D007211:Indoles; D009687:Nuclear Proteins; D011743:Pyrimidines; D057149:Ubiquitinated Proteins; D000251:Adenosine Triphosphatases; C404942:p97 ATPase