{"doi":"10.1016/j.jbc.2022.102826","title":"Diptoindonesin G, a new Hsp90 drug","abstract":"Hsp90 is a molecular chaperone that participates in protein folding, activation, and stabilization of substrate proteins. Since many diseases, including cancer, neurodegenerative diseases, and metabolic diseases, are caused by protein misfolding, drugs that inhibit Hsp90 are being pursued as potential targets for treatments. In the recent JBC Editor’s Pick by Donahue et al., the authors show that diptoindonesin G is a new Hsp90 inhibitor that promotes degradation of the estrogen receptor, an Hsp90 client, without inducing the heat shock response. Hsp90 is a molecular chaperone that participates in protein folding, activation, and stabilization of substrate proteins. Since many diseases, including cancer, neurodegenerative diseases, and metabolic diseases, are caused by protein misfolding, drugs that inhibit Hsp90 are being pursued as potential targets for treatments. In the recent JBC Editor’s Pick by Donahue et al., the authors show that diptoindonesin G is a new Hsp90 inhibitor that promotes degradation of the estrogen receptor, an Hsp90 client, without inducing the heat shock response. Diptoindonesin G is a middle domain HSP90 modulator for cancer treatmentJournal of Biological ChemistryVol. 298Issue 12PreviewHSP90 inhibitors can target many oncoproteins simultaneously, but none have made it through clinical trials due to dose-limiting toxicity and induction of heat shock response, leading to clinical resistance. We identified diptoindonesin G (dip G) as an HSP90 modulator that can promote degradation of HSP90 clients by binding to the middle domain of HSP90 (Kd = 0.13 ± 0.02 μM) without inducing heat shock response. This is likely because dip G does not interfere with the HSP90–HSF1 interaction like N-terminal inhibitors, maintaining HSF1 in a transcriptionally silent state. Full-Text PDF Open Access Hsp90 (heat shock protein 90) is an important and abundant ATP-dependent molecular chaperone, the expression of which is induced by heat shock and other cell stresses (1Schopf F.H. Biebl M.M. Buchner J. The HSP90 chaperone machinery.Nat. Rev. Mol. Cell Biol. 2017; 18: 345-360Crossref PubMed Scopus (862) Google Scholar, 2Mayer M.P. Le Breton L. Hsp90: breaking the symmetry.Mol. Cell. 2015; 58: 8-20Abstract Full Text Full Text PDF PubMed Scopus (123) Google Scholar). It performs essential functions in cellular proteostasis in eukaryotes by remodeling and activating client proteins such as signaling proteins, transcription factors, and regulatory kinases. In addition to promoting protein folding, Hsp90 directs misfolded proteins towards proteasome degradation pathways. Hsp90 functions as a dimer, with each protomer comprising an N-terminal ATP-binding domain, a middle domain, and a C-terminal domain involved in dimerization (Fig. 1). To participate in protein refolding, Hsp90 undergoes large conformational changes that are driven by ATP hydrolysis and modulated by more than 20 Hsp90 co-chaperones as well as the Hsp70 molecular chaperone (1Schopf F.H. Biebl M.M. Buchner J. The HSP90 chaperone machinery.Nat. Rev. Mol. Cell Biol. 2017; 18: 345-360Crossref PubMed Scopus (862) Google Scholar, 2Mayer M.P. Le Breton L. Hsp90: breaking the symmetry.Mol. Cell. 2015; 58: 8-20Abstract Full Text Full Text PDF PubMed Scopus (123) Google Scholar). Hsp90 has been extensively investigated as a potential target for cancer therapy since it promotes folding and activation of clients, such as the estrogen receptor (ER), that are upregulated in cancers and function as oncoproteins (3Sanchez J. Carter T.R. Cohen M.S. Blagg B.S.J. Old and new approaches to target the Hsp90 chaperone.Curr. Cancer Drug Targets. 2020; 20: 253-270Crossref PubMed Scopus (81) Google Scholar, 4Trepel J. Mollapour M. Giaccone G. Neckers L. Targeting the dynamic HSP90 complex in cancer.Nat. Rev. Cancer. 2010; 10: 537-549Crossref PubMed Scopus (1183) Google Scholar). Moreover, Hsp90 in cancerous cells is more active than normal tissues and this results in ‘oncogenic addiction’, ","journal":"Journal of Biological Chemistry","year":2022,"id":278386,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":7,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9545,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2022-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":685252,"name":"Sue Wickner","orcid":"0009-0005-9131-210X","position":1,"is_corresponding":false},{"id":950925,"name":"Anushka Wickramaratne","orcid":"0000-0001-5358-8272","position":0,"is_corresponding":true}],"reference_count":7,"raw_metadata":null,"created_at":"2026-07-19T00:28:47.357993Z","pmid":"36572186","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}