Abstract A034: Synthesis and biological activities of a novel series of “combi-molecules” designed to delay metabolic dealkylation prior to crossing the blood brain barrier in the context of optimizing their potency against glioblastoma multiforme
Bibliographic record
Abstract
Abstract Introduction. Glioblastoma multiforme (GBM) is the most aggressive form of primary brain tumor in adults with a survival of only 12-15 months. GBM stem cells contribute to resistance to the DNA-damaging first-line chemotherapy, temozolomide, which accounts for tumor recurrence and treatment failure. Amplification of epidermal growth factor receptor (EGFR) is one of the most common genetic alterations associated with GBM aggressiveness. Despite the evidence that EGFR-induced pathway represents an attractive therapeutic target in GBM, gefitinib, an orally active selective EGFR-tyrosine kinase inhibitor, showed only a limited potency in clinical trials. We previously showed that ZR2002, an aminoquinazoline “combi-molecule” designed to possess mixed EGFR tyrosine kinase inhibition and DNA damaging properties, induced submicromolar cytotoxic activity against GBM stem cells resistant to temozolomide and gefitinib. Significantly increased survival of mice harboring an intracranially implanted aggressive temozolomide-resistant tumour by comparison with the clinical treatment gefitinib. Furthermore, mass spectrometry imaging provided evidence of its ability to cross the blood–brain barrier but metabolites devoid of its critical 2-chloroethyl DNA alkylating function were observed. Given that the loss of DNA alkylating species may decrease efficacy in vivo, here we show a structure-activity relationship study toward structures with increased stability to metabolic dealkylation. Materials and methods. Three glioblastoma cells line (U87-wt, U87-EGFR and U87-EGFRvIII) were used to determine IC50 of the new molecules with SRB assay. CD1 mice were treated with a dose of 100mg/kg by oral gavage and analyzed after 3h. Drug metabolism was measured by LC-MS. Results. In vitro growth inhibitory showed that the new analogues have the same cytotoxicity profile as ZR2002. In vivo analysis in mice administered p.o. with the new analogues showed that our newly synthesized molecules were less metabolized than ZR2002 using the ratio of intact structure levels/over metabolites as a parameter that we defined as extent of metabolism. Furthermore, they were found to maintain good brain penetration. Conclusions. These results proved that we were able to design and synthesize combi-molecules that can escape metabolism and preserve the 2-chloroethyl in vivo, a group that is required for the dual activity of the combi-molecules. Importantly, the combi-molecules, despite the structural change, remain very water soluble and available orally. Citation Format: Ana Belen Fraga-Timiraos, Caterina Facchin, Anne-Laure Larroque-Lombard, Bertrand Jacques Jean-Claude. Synthesis and biological activities of a novel series of “combi-molecules” designed to delay metabolic dealkylation prior to crossing the blood brain barrier in the context of optimizing their potency against glioblastoma multiforme [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr A034.
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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) | 0.002 | 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".