Abstract 837: The unique profile of microtubule stability initiated by the taccalonolides leads to potent antitumor activities
Bibliographic record
Abstract
Abstract The taccalonolides are structurally distinct microtubule stabilizers purified from the roots and rhizomes of plants of the genus Tacca. The taccalonolides impart a unique mechanism of microtubule stabilization through covalent attachment to the 212-230 peptide of β-tubulin. The profound interprotofilament stability conferred by taccalonolide binding, as demonstrated by hydrogen deuterium exchange mass spectrometry, occurs independent of changes in the H7 or M-loops, which makes their effects different from other classes of microtubule stabilizers. This remarkable stability results in the formation of microtubules that are highly resistant to cold induced depolymerization or mechanical disruption. The covalent attachment of the taccalonolides to microtubules is proposed to be directly responsible for their strong cellular persistence and ability to circumvent multiple mechanisms of clinically relevant drug resistance, including expression of P-glycoprotein. We have isolated and characterized 66 new taccalonolides that range in potency from 0.37 nM to over 50 µM, allowing for detailed structure activity relationship studies. These studies demonstrate that epoxidation of the C22,23 double bond present in most naturally occurring taccalonolides is optimal for potency. A simple, one step oxidation reaction has been employed and increases the potency of 17 natural taccalonolides by as much as 700-fold. The new, potent taccalonolides show excellent antitumor activity against the MDA-MB-231 triple negative breast cancer xenograft model at cumulative doses as low as 0. 5 mg/kg. This exquisite in vivo potency facilitates antitumor evaluations from small quantities of material and allows administration in aqueous vehicles. Studies to further map the optimal interactions of the taccalonolide backbone with microtubules and identify a candidate for clinical development are in progress. Citation Format: April L. Risinger, Jing Li, Jiangnan Peng, Melissa J. Bennett, Cristina C. Rohena, David C. Schriemer, Susan L. Mooberry. The unique profile of microtubule stability initiated by the taccalonolides leads to potent antitumor activities. [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 837. doi:10.1158/1538-7445.AM2014-837
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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 | 0.000 |
| 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) | 0.000 | 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".