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Disruption of the Keap1-containing ubiquitination complex as an antioxidant therapy

Jonathan T Kern1, Mark Hannink, J Fred Hess

  • 1Neuroscience Drug Discovery, Merck Research Laboratories, Merck and Co., Inc., 770 Sumneytown Pike, PO Box 4, West Point, PA 19486, USA. jonathan_kern@merck.com

Current Topics in Medicinal Chemistry
|May 19, 2007
PubMed

Insights

Targeting Keap1 protein interactions could activate Nrf2, promoting antioxidant gene transcription. This approach may enhance cellular defense against oxidative stress disorders like cancer and Parkinson's disease.

Area of Science:

  • Biochemistry
  • Molecular Biology
  • Cellular Biology

Background:

  • Oxidative stress contributes to diseases like cancer and Parkinson's.
  • Antioxidant Response Element (ARE) genes protect cells from oxidative damage.
  • Nuclear factor erythroid 2-related factor 2 (Nrf2) activates ARE genes.
  • Kelch-like ECH-associated protein 1 (Keap1) regulates Nrf2 stability via ubiquitination and proteasomal degradation.

Purpose of the Study:

  • To propose a novel therapeutic strategy targeting the Keap1-Nrf2 pathway.
  • To explore small molecule modulation of Keap1 protein:protein interactions.
  • To enhance Nrf2 nuclear accumulation and subsequent ARE-dependent gene transcription.

Main Methods:

  • Elucidation of the structural interactions within the Keap1-ubiquitin ligase complex.
  • Hypothesizing small molecule-mediated disruption of Keap1 interactions.
  • Focus on promoting Nrf2 nuclear translocation.

Main Results:

  • Detailed structural studies of the Keap1 complex have been recently published.
  • This work proposes a mechanism for modulating Keap1 interactions.
  • The proposed mechanism aims to increase Nrf2 levels and activity.

Conclusions:

  • Modulating Keap1 protein:protein interactions is a potential therapeutic avenue.
  • This strategy could lead to increased nuclear accumulation of Nrf2.
  • Enhanced transcription of ARE-dependent genes may improve cellular resistance to oxidative stress.

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