PMID- 25564440 OWN - NLM STAT- MEDLINE DCOM- 20160316 LR - 20211109 IS - 1538-8514 (Electronic) IS - 1535-7163 (Print) IS - 1535-7163 (Linking) VI - 14 IP - 3 DP - 2015 Mar TI - Validation of the Hsp70-Bag3 protein-protein interaction as a potential therapeutic target in cancer. PG - 642-8 LID - 10.1158/1535-7163.MCT-14-0650 [doi] AB - 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 mumol/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. CI - (c)2015 American Association for Cancer Research. FAU - Li, Xiaokai AU - Li X AD - Department of Pharmaceutical Chemistry and the Institute for Neurodegenerative Disease, University of California at San Francisco, San Francisco, California. FAU - Colvin, Teresa AU - Colvin T AD - Department of Biochemistry, Boston University School of Medicine, Boston, Massachusetts. FAU - Rauch, Jennifer N AU - Rauch JN AD - Department of Pharmaceutical Chemistry and the Institute for Neurodegenerative Disease, University of California at San Francisco, San Francisco, California. FAU - Acosta-Alvear, Diego AU - Acosta-Alvear D AD - Department of Biochemistry and Biophysics, Howard Hughes Medical Institute, University of California at San Francisco, San Francisco, California. FAU - Kampmann, Martin AU - Kampmann M AD - Department of Molecular and Cellular Pharmacology, Howard Hughes Medical Institute, University of California at San Francisco, San Francisco, California. FAU - Dunyak, Bryan AU - Dunyak B AD - Department of Pharmaceutical Chemistry and the Institute for Neurodegenerative Disease, University of California at San Francisco, San Francisco, California. FAU - Hann, Byron AU - Hann B AD - Department of Medicine, Helen Diller Family Comprehensive Cancer Center, University of California at San Francisco, San Francisco, California. FAU - Aftab, Blake T AU - Aftab BT AD - Department of Medicine, Helen Diller Family Comprehensive Cancer Center, University of California at San Francisco, San Francisco, California. FAU - Murnane, Megan AU - Murnane M AD - Department of Medicine, Helen Diller Family Comprehensive Cancer Center, University of California at San Francisco, San Francisco, California. FAU - Cho, Min AU - Cho M AD - Department of Molecular and Cellular Pharmacology, Howard Hughes Medical Institute, University of California at San Francisco, San Francisco, California. FAU - Walter, Peter AU - Walter P AD - Department of Biochemistry and Biophysics, Howard Hughes Medical Institute, University of California at San Francisco, San Francisco, California. FAU - Weissman, Jonathan S AU - Weissman JS AD - Department of Molecular and Cellular Pharmacology, Howard Hughes Medical Institute, University of California at San Francisco, San Francisco, California. FAU - Sherman, Michael Y AU - Sherman MY AD - Department of Biochemistry, Boston University School of Medicine, Boston, Massachusetts. FAU - Gestwicki, Jason E AU - Gestwicki JE AD - Department of Pharmaceutical Chemistry and the Institute for Neurodegenerative Disease, University of California at San Francisco, San Francisco, California. Jason.Gestwicki@ucsf.edu. LA - eng GR - NIH CA081244/CA/NCI NIH HHS/United States GR - K99 CA181494/CA/NCI NIH HHS/United States GR - R01 NS059690/NS/NINDS NIH HHS/United States GR - R01 CA081244/CA/NCI NIH HHS/United States GR - K99CA181494/CA/NCI NIH HHS/United States GR - Howard Hughes Medical Institute/United States GR - NS059690/NS/NINDS NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't DEP - 20150106 PL - United States TA - Mol Cancer Ther JT - Molecular cancer therapeutics JID - 101132535 RN - 0 (Adaptor Proteins, Signal Transducing) RN - 0 (Antineoplastic Agents) RN - 0 (Apoptosis Regulatory Proteins) RN - 0 (BAG3 protein, human) RN - 0 (CDKN1A protein, human) RN - 0 (Cyclin-Dependent Kinase Inhibitor p21) RN - 0 (FOXM1 protein, human) RN - 0 (Forkhead Box Protein M1) RN - 0 (Forkhead Transcription Factors) RN - 0 (HSP70 Heat-Shock Proteins) RN - 0 (Proliferating Cell Nuclear Antigen) RN - 0 (p27 antigen) SB - IM MH - Adaptor Proteins, Signal Transducing/*metabolism MH - Animals MH - Antineoplastic Agents/pharmacology MH - Apoptosis Regulatory Proteins/*metabolism MH - Cell Line, Tumor MH - Cell Proliferation/drug effects MH - Cyclin-Dependent Kinase Inhibitor p21/metabolism MH - Forkhead Box Protein M1 MH - Forkhead Transcription Factors/metabolism MH - Gene Expression Regulation, Neoplastic/drug effects MH - HSP70 Heat-Shock Proteins/*metabolism MH - HT29 Cells MH - HeLa Cells MH - Humans MH - MCF-7 Cells MH - Mice MH - Proliferating Cell Nuclear Antigen/metabolism MH - Protein Interaction Domains and Motifs/*physiology PMC - PMC4456214 MID - NIHMS653580 COIS- Conflict of Interest: The authors report no conflicts of interest EDAT- 2015/01/08 06:00 MHDA- 2016/03/17 06:00 PMCR- 2016/03/01 CRDT- 2015/01/08 06:00 PHST- 2014/08/22 00:00 [received] PHST- 2014/12/16 00:00 [accepted] PHST- 2015/01/08 06:00 [entrez] PHST- 2015/01/08 06:00 [pubmed] PHST- 2016/03/17 06:00 [medline] PHST- 2016/03/01 00:00 [pmc-release] AID - 1535-7163.MCT-14-0650 [pii] AID - 10.1158/1535-7163.MCT-14-0650 [doi] PST - ppublish SO - Mol Cancer Ther. 2015 Mar;14(3):642-8. doi: 10.1158/1535-7163.MCT-14-0650. Epub 2015 Jan 6.