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

Xiaokai Li, Teresa Colvin, Jennifer N. Rauch, Diego Acosta-Alvear, Martin Kampmann, Bryan Dunyak, Byron Hann, Blake T. Aftab, Megan Murnane, Min Cho, Peter Walter, Jonathan S. Weissman, Michael Y. Sherman, Jason E. Gestwicki

Research output: Contribution to journalArticlepeer-review

99 Scopus citations

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.

Original languageEnglish
Pages (from-to)642-648
Number of pages7
JournalMolecular Cancer Therapeutics
Volume14
Issue number3
DOIs
StatePublished - Mar 2015
Externally publishedYes

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