Structure-Guided Discovery of Subtype Selective SIRT6 Inhibitors with a β-Carboline Skeleton for the Treatment of Breast Cancer
Bibliographic record
Abstract
SIRT6 promotes the progression of breast cancer by inducing drug resistance by reinforcing DNA damage repair mechanisms. This study utilized a combination of high-throughput virtual screening and FLUOR DE LYS assays. Hit 14 which features a novel β-carboline skeleton as a potent SIRT6 inhibitor was found. Subsequent structure-guided optimization led to the synthesis of 60 3,6,9-position modified derivatives based on the differences analysis of SIRTs family proteins. Of which, 10d inhibited the deacetylase activity of SIRT6, with an IC 50 of 5.81 μM and more than 27 times subtype selectivity. Phe64, Met157, and Ser56 were identified as the key residues. Moreover, 10d suppressed breast cancer cell proliferation, migration, invasion, and induced apoptosis in MCF-7 cells by disrupting the DNA damage repair pathway. Additionally, 10d demonstrated a safe and effective antibreast cancer effect in vivo, presenting a promising strategy for the treatment of breast cancer by targeting SIRT6.
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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) | 0.001 | 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 | 0.001 |
| Insufficient payload (model declined to judge) | 0.002 | 0.001 |
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".