Incorporation of histone deacetylase inhibition into the structure of a nuclear receptor agonist
Bibliographic record
Abstract
1,25-dihydroxyvitamin D(3) (1,25D) regulates gene expression by signaling through the nuclear vitamin D receptor (VDR) transcription factor and exhibits calcium homeostatic, anticancer, and immunomodulatory properties. Histone deacetylase inhibitors (HDACis) alter nuclear and cytoplasmic protein acetylation, modify gene expression, and have potential for treatment of cancer and other indications. The function of nuclear receptor ligands, including 1,25D, can be enhanced in combination with HDACi. We designed triciferol, a hybrid molecule in which the 1,25D side chain was replaced with the dienyl hydroxamic acid of HDACi trichostatin A. Triciferol binds directly to the VDR, and functions as an agonist with 1,25D-like potency on several 1,25D target genes. Moreover, unlike 1,25D, triciferol induces marked tubulin hyperacetylation, and augments histone acetylation at concentrations that largely overlap those where VDR agonism is observed. Triciferol also exhibits more efficacious antiproliferative and cytotoxic activities than 1,25D in four cancer cell models in vitro. The bifunctionality of triciferol is notable because (i) the HDACi activity is generated by modifying the 1,25D side chain without resorting to linker technology and (ii) 1,25D and HDACi have sympathetic, but very distinct biochemical targets; the hydrophobic VDR ligand binding domain and the active sites of HDACs, which are zinc metalloenzymes. These studies demonstrate the feasibility of combining HDAC inhibition with nuclear receptor agonism to enhance their therapeutic potential.
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How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.001 | 0.001 |
| 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 | 0.002 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.000 | 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 teacher head, 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".