Identification and Characterization of Novel Nrf2 Inducers Designed to Target the Intervening Region of Keap1
Bibliographic record
Abstract
Transcription factor Nrf2 regulates a battery of genes encoding detoxifying enzymes. Under basal conditions, Nrf2 is sequestered in the cytoplasm by a protein known as Keap1. In response to oxidative stress, Keap1-mediated ubiquitination of Nrf2 is decreased significantly and the Nrf2 pathway is turned on. Residues C273 and C288 at the intervening region (IVR) domain of Keap1 are necessary for Keap1 to repress Nrf2, indicating a critical role of the IVR domain in the functional interaction of Keap1 with Nrf2. To identify chemical modulator targeting the IVR domain of Keap1, we built a 3D structural model of the Keap1 IVR domain and demonstrated this structural model is effective in retrieving novel Nrf2 inducers from chemical databases, BM10, 31, and 40 increase concentration of nuclear Nrf2, with a potency comparable to that of sulforaphane. We showed C297S mutation partially abolished the Nrf2-inducing effect of BM31, suggesting BM31 may target C297 in the IVR domain of Keap1. Further, BM31 and BM40 potently induce expression of ARE-regulated enzyme gamma-glutamylcysteine synthetase. We demonstrated that BM31 provides protections for the MCF-7 cells from cytotoxic damage of carcinogen benzo[a]pyrene.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.001 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".