Updated project metadata. HSP90 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 without inducing heat shock response. Although dip G does not bind to the ligand binding domain (LBD) of estrogen receptor (ER), it promotes degradation of ER in breast cancer cells. We further showed that treatment of ER LBD mutantexpressing cells with dip G promoted degradation of wild type and mutant ER with similar efficacy, downregulated ER-regulated gene expression, and inhibited cell proliferation. Our data suggest that dip G circumvents some obstacles associated with HSP90 inhibition and may be developed as a new therapeutic avenue to various cancers, particularly endocrine resistant breast cancer harboring ESR1 mutations