Apr 4, 2020

Obtusaquinone is a cysteine modifying compound that targets Keap1 for degradation

BioRxiv : the Preprint Server for Biology
Christian E BadrB. A. Tannous

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, pharmacokinetic analysis, as well as mouse xenograft models to develop and validate novel OBT analogs and charaterize the molecular mechanism of action of OBT. We here show that OBT and analogs, which have improved pharmacological properties, bind to cysteine residues with particular affinity to cysteine-rich Keap1, a member of the CUL3 ubiquitin ligase complex. This binding promotes an overall stress response and results in ubiquitination and proteasomal degradation of Keap1 and downstream activation of the Nrf2 pathway.

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Mentioned in this Paper

SYCP1 protein, human
Pachytene
Establishment and Maintenance of Localization
Meiotic Cell Cycle
Patterns
Histone antigen
Pachytene Stage
Genome
Recombination, Genetic
Lysine

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