title: Discovery of a First-in-Class, Potent, Selective, and Orally Bioavailable Inhibitor of the p97 AAA ATPase (CB-5083).
abstract: The AAA-ATPase p97 plays vital roles in mechanisms of protein homeostasis, including ubiquitin-proteasome system (UPS) mediated protein degradation, endoplasmic reticulum-associated degradation (ERAD), and autophagy. Herein we describe our lead optimization efforts focused on in vitro potency, ADME, and pharmaceutical properties that led to the discovery of a potent, ATP-competitive, D2-selective, and orally bioavailable p97 inhibitor 71, CB-5083. Treatment of tumor cells with 71 leads to significant accumulation of markers associated with inhibition of UPS and ERAD functions, which induces irresolvable proteotoxic stress and cell death. In tumor bearing mice, oral administration of 71 causes rapid accumulation of markers of the unfolded protein response (UPR) and subsequently induces apoptosis leading to sustained antitumor activity in in vivo xenograft models of both solid and hematological tumors. 71 has been taken into phase 1 clinical trials in patients with multiple myeloma and solid tumors.
authors.affiliation: Cleave Biosciences Inc. , 866 Malcom Road, Burlingame, California 94010, United States.
authors.forename: Han-Jie
authors.initials: HJ
authors.lastname: Zhou
authors.affiliation: Cleave Biosciences Inc. , 866 Malcom Road, Burlingame, California 94010, United States.
authors.forename: Jinhai
authors.initials: J
authors.lastname: Wang
authors.affiliation: Cleave Biosciences Inc. , 866 Malcom Road, Burlingame, California 94010, United States.
authors.forename: Bing
authors.initials: B
authors.lastname: Yao
authors.affiliation: Cleave Biosciences Inc. , 866 Malcom Road, Burlingame, California 94010, United States.
authors.forename: Steve
authors.initials: S
authors.lastname: Wong
authors.affiliation: Cleave Biosciences Inc. , 866 Malcom Road, Burlingame, California 94010, United States.
authors.forename: Stevan
authors.initials: S
authors.lastname: Djakovic
authors.affiliation: Cleave Biosciences Inc. , 866 Malcom Road, Burlingame, California 94010, United States.
authors.forename: Brajesh
authors.initials: B
authors.lastname: Kumar
authors.affiliation: Cleave Biosciences Inc. , 866 Malcom Road, Burlingame, California 94010, United States.
authors.forename: Julie
authors.initials: J
authors.lastname: Rice
authors.affiliation: Cleave Biosciences Inc. , 866 Malcom Road, Burlingame, California 94010, United States.
authors.forename: Eduardo
authors.initials: E
authors.lastname: Valle
authors.affiliation: Cleave Biosciences Inc. , 866 Malcom Road, Burlingame, California 94010, United States.
authors.forename: Ferdie
authors.initials: F
authors.lastname: Soriano
authors.affiliation: Cleave Biosciences Inc. , 866 Malcom Road, Burlingame, California 94010, United States.
authors.forename: Mary-Kamala
authors.initials: MK
authors.lastname: Menon
authors.affiliation: Cleave Biosciences Inc. , 866 Malcom Road, Burlingame, California 94010, United States.
authors.forename: Antonett
authors.initials: A
authors.lastname: Madriaga
authors.affiliation: Cleave Biosciences Inc. , 866 Malcom Road, Burlingame, California 94010, United States.
authors.forename: Szerenke
authors.initials: S
authors.lastname: Kiss von Soly
authors.affiliation: Cleave Biosciences Inc. , 866 Malcom Road, Burlingame, California 94010, United States.
authors.forename: Abhinav
authors.initials: A
authors.lastname: Kumar
authors.affiliation: Cleave Biosciences Inc. , 866 Malcom Road, Burlingame, California 94010, United States.
authors.forename: Francesco
authors.initials: F
authors.lastname: Parlati
authors.affiliation: Cleave Biosciences Inc. , 866 Malcom Road, Burlingame, California 94010, United States.
authors.forename: F Michael
authors.initials: FM
authors.lastname: Yakes
authors.affiliation: Cleave Biosciences Inc. , 866 Malcom Road, Burlingame, California 94010, United States.
authors.forename: Laura
authors.initials: L
authors.lastname: Shawver
authors.affiliation: Cleave Biosciences Inc. , 866 Malcom Road, Burlingame, California 94010, United States.
authors.forename: Ronan
authors.initials: R
authors.lastname: Le Moigne
authors.affiliation: Cleave Biosciences Inc. , 866 Malcom Road, Burlingame, California 94010, United States.
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Anderson
authors.affiliation: Cleave Biosciences Inc. , 866 Malcom Road, Burlingame, California 94010, United States.
authors.forename: Mark
authors.initials: M
authors.lastname: Rolfe
authors.affiliation: Cleave Biosciences Inc. , 866 Malcom Road, Burlingame, California 94010, United States.
authors.forename: David
authors.initials: D
authors.lastname: Wustrow
mesh_terms: D000251:Adenosine Triphosphatases / Q000037:antagonists & inhibitors*; D000284:Administration, Oral; D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology; D017209:Apoptosis; D001682:Biological Availability; D045744:Cell Line, Tumor; D004354:Drug Screening Assays, Antitumor; D005260:Female; D064593:Heterografts; D006801:Humans; D007211:Indoles / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology; D008819:Mice, Nude; D062105:Molecular Docking Simulation; D009368:Neoplasm Transplantation; D009687:Nuclear Proteins / Q000037:antagonists & inhibitors*; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D011743:Pyrimidines / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology; D013329:Structure-Activity Relationship; D025801:Ubiquitin / Q000378:metabolism; D056811:Unfolded Protein Response
chemical_list: D000970:Antineoplastic Agents; C000606272:CB-5083; D007211:Indoles; D009687:Nuclear Proteins; D011743:Pyrimidines; D025801:Ubiquitin; D046988:Proteasome Endopeptidase Complex; D000251:Adenosine Triphosphatases; C404942:p97 ATPase