Diptoindonesin G is a middle domain HSP90 modulator for cancer treatment.

ABSTRACT: 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 (K_d = 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. We found that binding of dip G to HSP90 promotes degradation of HSP90 client protein estrogen receptor α (ER), a major oncogenic driver protein in most breast cancers. Mutations in the ER ligand-binding domain (

SUBMITTER: Donahue K 

PROVIDER: S-EPMC9771721 | biostudies-literature | 2022 Dec

REPOSITORIES: biostudies-literature