Abstract 4575: Structure-based design, synthesis and biological testing of highly potent semi-synthetic epipodophyllotoxin-derived hybrid etoposide analogs
Bibliographic record
Abstract
Abstract Drugs that target DNA topoisomerase II and interact with DNA represent two mechanistically distinct and clinically important classes of anticancer drugs. Using a structure-based design approach a series of epipodophyllotoxin-derived hybrid etoposide analogs were designed, synthesized and biologically characterized. It was hypothesized that combining an epipodophyllotoxin moiety that could interact with specific protein residues on topoisomerase II and DNA-interacting moieties in the same molecule would produce much stronger binding and yield more potent and wide spectrum cytotoxic anticancer drugs. Because the hybrids have unique dual targeting mechanisms, cancer cells should be much less able to develop resistance. The most potent hybrid had a mean GI50 in the NCI-60 cell screen much lower than etoposide. The compounds were much less cross-resistant to a K562-derived etoposide-resistant cell line. All of the hybrids tested targeted topoisomerase II as evidenced by their ability to inhibit kDNA decatenation, to produce linear DNA in a DNA cleavage assay and to form covalent topoisomerase II-DNA covalent complexes in a cellular ICE assay. The DNA double strand breaks the hybrids produced in a cellular γH2AX assay and the G2/M cell cycle blocks were also characteristic of topoisomerase II-targeted drugs. Cell cycle analysis was also used to characterize the targets. A COMPARE analysis indicated that the hybrids had NCI 60-cell growth inhibition profiles of both etoposide and the DNA-interacting moieties from which they were derived. This data supports the conclusion that the hybrids displayed characteristics that were consistent with having targeted both topoisomerase II and DNA. Support: CIHR and a Canada Research Chair in Drug Development. Citation Format: Brian B. Hasinoff. Structure-based design, synthesis and biological testing of highly potent semi-synthetic epipodophyllotoxin-derived hybrid etoposide analogs. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4575. doi:10.1158/1538-7445.AM2014-4575
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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".