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Cyclic vinyl sulfones activate NRF2 to protect from oxidative stress-induced programmed necrosis

Pavel Davidovich1, Dmitriy Nikolaev2, Raniya Khadiullina3

  • 1Trinity College, Dublin, Ireland.

Bioorganic & Medicinal Chemistry Letters
|December 7, 2024
PubMed

Insights

Cyclic vinyl sulfones, like LCB1353, activate the NRF2 pathway, stabilizing NRF2 protein and upregulating its target genes. These compounds show promise in protecting cells from oxidative stress and ferroptosis.

Area of Science:

  • Molecular Biology
  • Cellular Biology
  • Pharmacology

Background:

  • The NRF2 transcriptional factor regulates cellular responses to oxidative stress.
  • NRF2 levels are tightly controlled by proteasomal degradation, involving KEAP1 and the E3 ligase Cullin-3.
  • Cyclic vinyl sulfone derivatives have demonstrated anti-inflammatory properties, but their mechanism of action was unclear.

Purpose of the Study:

  • To investigate cyclic vinyl sulfone derivatives as potential NRF2 activating probes.
  • To elucidate the mechanism underlying the anti-inflammatory effects of these compounds.
  • To evaluate the protective effects of LCB1353 against oxidative stress-induced cell death.

Main Methods:

  • Examination of model cyclic vinyl sulfone derivatives.
  • Assessment of NRF2 protein stabilization and target gene upregulation.
  • Evaluation of cell viability in non-small cell lung cancer cells (H1299) under ferroptotic conditions induced by RSL3.

Main Results:

  • The naphthohydroquinone derivative LCB1353 was found to efficiently stabilize NRF2 protein levels.
  • LCB1353 treatment led to the upregulation of NRF2 target genes.
  • At 5-10 µM, LCB1353 significantly protected H1299 cells from RSL3-induced ferroptotic death, reducing cell death from 90% to 5%.

Conclusions:

  • Cyclic vinyl sulfones, exemplified by LCB1353, are effective NRF2 activators.
  • LCB1353 demonstrates potent protective effects against ferroptosis.
  • These compounds represent promising scaffolds for developing therapeutic agents against conditions involving oxidative stress and inflammation.
Keywords:
Cell deathCyclic vinyl sulfonesFerroptosisNRF2Programmed necrosisProtection

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