{"doi":"10.1016/j.jbc.2020.100211","title":"Dealing with difficult clients via personalized chaperone inhibitors","abstract":"The importance of molecular chaperones in cancer is well established, yet several chaperone inhibitors have failed in clinical trials due to toxicity. Recent efforts have focused on targeting chaperone function in cancer by either manipulating the “chaperone code” or inhibiting helper cochaperones, such as DNAJA1. Tong et al. identify a novel inhibitor that specifically disrupts DNAJA1's interaction with p53, promoting p53 degradation. This finding highlights specific DNAJA1 interactions with the potential for less toxicity compared to traditional chaperone inhibitors. The importance of molecular chaperones in cancer is well established, yet several chaperone inhibitors have failed in clinical trials due to toxicity. Recent efforts have focused on targeting chaperone function in cancer by either manipulating the “chaperone code” or inhibiting helper cochaperones, such as DNAJA1. Tong et al. identify a novel inhibitor that specifically disrupts DNAJA1's interaction with p53, promoting p53 degradation. This finding highlights specific DNAJA1 interactions with the potential for less toxicity compared to traditional chaperone inhibitors. Molecular chaperones are highly expressed proteins that act as custodians of the cell, helping to fold a large fraction of the proteome. The most well studied of these are Hsp70 and Hsp90, which are critical for cell viability (1Rosenzweig R. Nillegoda N.B. Mayer M.P. Bukau B. The Hsp70 chaperone network.Nat. Rev. Mol. Cell Biol. 2019; 20: 665-680Crossref PubMed Scopus (271) Google Scholar). Hsp70 works at the initial stages of folding, binding newly synthesized and denatured proteins. In contrast, Hsp90 binds clients after they have been processed by Hsp70, promoting protein maturation and activation. Due to their ability to stabilize selected oncoproteins, significant research into development of chaperone-targeting anticancer therapeutics has been pursued. Unfortunately, many of the molecules identified to date have failed in patient trials due to toxicity, presumably due to consequences of chaperone inhibition in healthy cells (1Rosenzweig R. Nillegoda N.B. Mayer M.P. Bukau B. The Hsp70 chaperone network.Nat. Rev. Mol. Cell Biol. 2019; 20: 665-680Crossref PubMed Scopus (271) Google Scholar). The lack of clinical success of chaperone inhibitors has led researchers to begin to focus on novel ways to modulate chaperone function rather than completely abolish it. One direction has been to explore manipulation of the chaperone code, the posttranslational modifications that regulate chaperone function (2Nitika Porter C.M. Truman A.W. Truttmann M.C. Post-translational modifications of Hsp70 family proteins: expanding the chaperone code.J. Biol. Chem. 2020; 295: 10689-10708Abstract Full Text Full Text PDF PubMed Scopus (43) Google Scholar). Another approach has been to explore the role of helper “co-chaperones” and the impact of inhibiting specific cochaperone interactions (Fig. 1). For example, Hsp70 requires a large suite of cochaperones for function. These cochaperones bind unfolded clients and direct them to Hsp70 for folding (1Rosenzweig R. Nillegoda N.B. Mayer M.P. Bukau B. The Hsp70 chaperone network.Nat. Rev. Mol. Cell Biol. 2019; 20: 665-680Crossref PubMed Scopus (271) Google Scholar, 3Kampinga H.H. Craig E.A. The HSP70 chaperone machinery: J proteins as drivers of functional specificity.Nat. Rev. Mol. Cell Biol. 2010; 11: 579-592Crossref PubMed Scopus (1036) Google Scholar). Additionally, cochaperones such as DNAJA1 are able to activate Hsp70 activity directly by binding Hsp70 and stimulating the Hsp70 ATPase cycle required for chaperone function. An early indication that Hsp70 cochaperones may play a role in cancer came in 2016 when Parrales and colleagues uncovered a connection between the mevalonate metabolic pathway and the activity and stability of mutant p53, a well-established tumor suppressor (4Parrales A. Ranjan A. Iyer S.V. Padhye S. Weir S.J. Roy A. Iwakuma T. DNAJA1 controls the ","journal":"Journal of Biological Chemistry","year":2021,"id":204811,"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":3,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9495,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2021-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":444005,"name":"Andrew W. Truman","orcid":"0000-0002-6409-3723","position":0,"is_corresponding":true}],"reference_count":10,"raw_metadata":null,"created_at":"2026-07-18T23:51:30.197308Z","pmid":"33837724","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":[]}