{"database":"biostudies-literature","file_versions":[],"scores":null,"additional":{"submitter":["Ferguson ID"],"funding":["Multiple Myeloma Research Foundation","NCI NIH HHS","NINDS NIH HHS","University of California","National Institutes of Health","US Department of Defense","Gabrielle's Angel Foundation for Cancer Research","NIGMS NIH HHS"],"pagination":["1288-1302.e7"],"full_dataset_link":["https://www.ebi.ac.uk/biostudies/studies/S-EPMC9434701"],"repository":["biostudies-literature"],"omics_type":["Unknown"],"volume":["29(8)"],"pubmed_abstract":["Proteasome inhibitor (PI) resistance remains a central challenge in multiple myeloma. To identify pathways mediating resistance, we first mapped proteasome-associated genetic co-dependencies. We identified heat shock protein 70 (HSP70) chaperones as potential targets, consistent with proposed mechanisms of myeloma cells overcoming PI-induced stress. We therefore explored allosteric HSP70 inhibitors (JG compounds) as myeloma therapeutics. JG compounds exhibited increased efficacy against acquired and intrinsic PI-resistant myeloma models, unlike HSP90 inhibition. Shotgun and pulsed SILAC mass spectrometry demonstrated that JGs unexpectedly impact myeloma proteostasis by destabilizing the 55S mitoribosome. Our data suggest JGs have the most pronounced anti-myeloma effect not through inhibiti"],"journal":["Cell chemical biology"],"pubmed_title":["Allosteric HSP70 inhibitors perturb mitochondrial proteostasis and overcome proteasome inhibitor resistance in multiple myeloma."],"pmcid":["PMC9434701"],"funding_grant_id":["F32 CA236156","U54 CA224018","DP2 OD022552","P30 CA082103","F32CA236156","T32 GM145460","R01 CA226851","K08 CA184116","DoD PC180716","R01 NS059690"],"pubmed_authors":["Lin YT","Shao H","Patino Escobar B","Lam C","Wang D","Tuomivaara ST","Kishishita A","Steri V","Phojanakong P","Ferguson ID","Kasap C","Van Ness B","Gestwicki JE","Hale M","Mandal K","Driessen C","Wiita AP","Hann B","Tharp KM","Mariano MC"],"additional_accession":[]},"is_claimable":false,"name":"Allosteric HSP70 inhibitors perturb mitochondrial proteostasis and overcome proteasome inhibitor resistance in multiple myeloma.","description":"Proteasome inhibitor (PI) resistance remains a central challenge in multiple myeloma. To identify pathways mediating resistance, we first mapped proteasome-associated genetic co-dependencies. We identified heat shock protein 70 (HSP70) chaperones as potential targets, consistent with proposed mechanisms of myeloma cells overcoming PI-induced stress. We therefore explored allosteric HSP70 inhibitors (JG compounds) as myeloma therapeutics. JG compounds exhibited increased efficacy against acquired and intrinsic PI-resistant myeloma models, unlike HSP90 inhibition. Shotgun and pulsed SILAC mass spectrometry demonstrated that JGs unexpectedly impact myeloma proteostasis by destabilizing the 55S mitoribosome. Our data suggest JGs have the most pronounced anti-myeloma effect not through inhibiti","dates":{"release":"2022-01-01T00:00:00Z","publication":"2022 Aug","modification":"2026-05-28T01:56:15.976Z","creation":"2025-04-04T20:28:39.026Z"},"accession":"S-EPMC9434701","cross_references":{"pubmed":["35853457"],"doi":["10.1016/j.chembiol.2022.06.010"]}}