Antitumor activity and pharmacologic characterization of the depsipeptide analog as a novel histone deacetylase/ phosphatidylinositol 3‐kinase dual inhibitor
Why this work is in the frame
A frame that forgets how it found something cannot be audited. These are the routes that admitted this work.
Bibliographic record
Abstract
Histone deacetylase (HDAC)/phosphatidylinositol 3-kinase (PI3K) dual inhibition is a promising strategy for the treatment of intractable cancers because of the advantages of overcoming potential resistance and showing synergistic effects. Therefore, development of an HDAC/PI3K dual inhibitor is reasonably attractive. Romidepsin (FK228, depsipeptide) is a potent HDAC inhibitor. We previously reported that depsipeptide and its analogs have an additional activity as PI3K inhibitors and are defined as HDAC/PI3K dual inhibitors. Subsequently, we identified FK-A11 as the most potent analog and reported its biochemical, biological, and structural properties as an HDAC/PI3K dual inhibitor. In this study, we reveal the in vitro and in vivo efficacy of FK-A11 in HT1080 fibrosarcoma and PC3 prostate cancer cell xenograft mouse models. FK-A11 showed in vivo antitumor activity by both i.v. and i.p. administration in a dose-dependent manner. In both xenograft models, FK-A11 showed superior antitumor effects compared to other depsipeptide analogs in accordance with in vitro anti-cell proliferation effects and the potency of HDAC/PI3K dual inhibition. In addition, we showed evidence of HDAC/PI3K dual inhibition accompanying antitumor efficacy in xenograft tumor tissues by immunohistochemistry. We also detailed pharmacokinetic characterization of FK-A11 in mice. These findings will be essential for guiding further preclinical and clinical studies.
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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 | 0.000 | 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 | 0.001 | 0.002 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.001 | 0.001 |
| 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 it