Validation of the Hsp70-Bag3 protein-protein interaction as a potential therapeutic target in cancer

• Published in: Molecular cancer therapeutics Vol. 14; no. 3; pp. 642 - 648
• Main Authors: Li, Xiaokai, Colvin, Teresa, Rauch, Jennifer N, Acosta-Alvear, Diego, Kampmann, Martin, Dunyak, Bryan, Hann, Byron, Aftab, Blake T, Murnane, Megan, Cho, Min, Walter, Peter, Weissman, Jonathan S, Sherman, Michael Y, Gestwicki, Jason E
• Format: Journal Article
• Language: English
• Published: United States 01.03.2015
• Subjects: Adaptor Proteins, Signal Transducing - metabolism; Animals; Antineoplastic Agents - pharmacology; Apoptosis Regulatory Proteins - metabolism; Cell Line, Tumor; Cell Proliferation - drug effects; Cyclin-Dependent Kinase Inhibitor p21 - metabolism; Forkhead Box Protein M1; Forkhead Transcription Factors - metabolism; Gene Expression Regulation, Neoplastic - drug effects; HeLa Cells; HSP70 Heat-Shock Proteins - metabolism; HT29 Cells; Humans; MCF-7 Cells; Mice; Proliferating Cell Nuclear Antigen - metabolism; Protein Interaction Domains and Motifs - physiology
• ISSN: 1535-7163; 1538-8514
• DOI: 10.1158/1535-7163.mct-14-0650

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.