title: Validation of the Hsp70-Bag3 protein-protein interaction as a potential therapeutic target in cancer.
abstract: Hsp70 is a stress-inducible molecular chaperone that is required for cancer development at several steps. Targeting the active site of Hsp70 has proven relatively challenging, driving interest in alternative approaches. Hsp70 collaborates with the Bcl2-associated athanogene 3 (Bag3) to promote cell survival through multiple pathways, including FoxM1. Therefore, inhibitors of the Hsp70-Bag3 protein-protein interaction (PPI) may provide a noncanonical way to target this chaperone. We report that JG-98, an allosteric inhibitor of this PPI, indeed has antiproliferative activity (EC50 values between 0.3 and 4 μmol/L) across cancer cell lines from multiple origins. JG-98 destabilized FoxM1 and relieved suppression of downstream effectors, including p21 and p27. On the basis of these findings, JG-98 was evaluated in mice for pharmacokinetics, tolerability, and activity in two xenograft models. The results suggested that the Hsp70-Bag3 interaction may be a promising, new target for anticancer therapy.
authors.affiliation: Department of Pharmaceutical Chemistry and the Institute for Neurodegenerative Disease, University of California at San Francisco, San Francisco, California.
authors.forename: Xiaokai
authors.initials: X
authors.lastname: Li
authors.affiliation: Department of Biochemistry, Boston University School of Medicine, Boston, Massachusetts.
authors.forename: Teresa
authors.initials: T
authors.lastname: Colvin
authors.affiliation: Department of Pharmaceutical Chemistry and the Institute for Neurodegenerative Disease, University of California at San Francisco, San Francisco, California.
authors.forename: Jennifer N
authors.initials: JN
authors.lastname: Rauch
authors.affiliation: Department of Biochemistry and Biophysics, Howard Hughes Medical Institute, University of California at San Francisco, San Francisco, California.
authors.forename: Diego
authors.initials: D
authors.lastname: Acosta-Alvear
authors.affiliation: Department of Molecular and Cellular Pharmacology, Howard Hughes Medical Institute, University of California at San Francisco, San Francisco, California.
authors.forename: Martin
authors.initials: M
authors.lastname: Kampmann
authors.affiliation: Department of Pharmaceutical Chemistry and the Institute for Neurodegenerative Disease, University of California at San Francisco, San Francisco, California.
authors.forename: Bryan
authors.initials: B
authors.lastname: Dunyak
authors.affiliation: Department of Medicine, Helen Diller Family Comprehensive Cancer Center, University of California at San Francisco, San Francisco, California.
authors.forename: Byron
authors.initials: B
authors.lastname: Hann
authors.affiliation: Department of Medicine, Helen Diller Family Comprehensive Cancer Center, University of California at San Francisco, San Francisco, California.
authors.forename: Blake T
authors.initials: BT
authors.lastname: Aftab
authors.affiliation: Department of Medicine, Helen Diller Family Comprehensive Cancer Center, University of California at San Francisco, San Francisco, California.
authors.forename: Megan
authors.initials: M
authors.lastname: Murnane
authors.affiliation: Department of Molecular and Cellular Pharmacology, Howard Hughes Medical Institute, University of California at San Francisco, San Francisco, California.
authors.forename: Min
authors.initials: M
authors.lastname: Cho
authors.affiliation: Department of Biochemistry and Biophysics, Howard Hughes Medical Institute, University of California at San Francisco, San Francisco, California.
authors.forename: Peter
authors.initials: P
authors.lastname: Walter
authors.affiliation: Department of Molecular and Cellular Pharmacology, Howard Hughes Medical Institute, University of California at San Francisco, San Francisco, California.
authors.forename: Jonathan S
authors.initials: JS
authors.lastname: Weissman
authors.affiliation: Department of Biochemistry, Boston University School of Medicine, Boston, Massachusetts.
authors.forename: Michael Y
authors.initials: MY
authors.lastname: Sherman
authors.affiliation: Department of Pharmaceutical Chemistry and the Institute for Neurodegenerative Disease, University of California at San Francisco, San Francisco, California. Jason.Gestwicki@ucsf.edu.
authors.forename: Jason E
authors.initials: JE
authors.lastname: Gestwicki
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism*; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism; D000072278:Forkhead Box Protein M1; D051858:Forkhead Transcription Factors / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D018840:HSP70 Heat-Shock Proteins / Q000378:metabolism*; D019073:HT29 Cells; D006367:HeLa Cells; D006801:Humans; D061986:MCF-7 Cells; D051379:Mice; D018809:Proliferating Cell Nuclear Antigen / Q000378:metabolism; D054730:Protein Interaction Domains and Motifs / Q000502:physiology*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D000970:Antineoplastic Agents; D051017:Apoptosis Regulatory Proteins; C414431:BAG3 protein, human; C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; C107585:FOXM1 protein, human; D000072278:Forkhead Box Protein M1; D051858:Forkhead Transcription Factors; D018840:HSP70 Heat-Shock Proteins; D018809:Proliferating Cell Nuclear Antigen; C413374:p27 antigen