Obtusaquinone: A Cysteine-Modifying Compound That Targets Keap1 for Degradation.

ABSTRACT: We have previously identified the natural product obtusaquinone (OBT) as a potent antineoplastic agent with promising in vivo activity in glioblastoma and breast cancer through the activation of oxidative stress; however, the molecular properties of this compound remained elusive. We used a multidisciplinary approach comprising medicinal chemistry, quantitative mass spectrometry-based proteomics, functional studies in cancer cells, and pharmacokinetic analysis, as well as mouse xenograft models to develop and validate novel OBT analogs and characterize the molecular mechanism of action of OBT. We show here that OBT binds to cysteine residues with a particular affinity to cysteine-rich Keap1, a member of the CUL3 ubiquitin ligase complex. This binding promotes an overall stress respo

SUBMITTER: Badr CE 

PROVIDER: S-EPMC7995447 | biostudies-literature | 2020 Jun

REPOSITORIES: biostudies-literature