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
Notice bibliographique
Résumé
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.
Récupéré en direct depuis OpenAlex et désinversé. Les résumés ne sont pas conservés dans cette base de données : les index inversés représentent 8,6 Go des 9,3 Go de texte de la base, et le serveur dispose de 13 Go libres.
Comment cette classification a été obtenuedéplier
Prédiction machine sur la base complète
Imitation des enseignantsNi prévalence calibrée, ni vérité terrain. Validation humaine à venir. Le volet Gemma est une étiquette directe du modèle pour chaque travail de la base, lue sur la notice réduite au titre. Le volet Codex est un classifieur appris des 10 348 étiquettes directes de Codex et calibré sur les taux pondérés de l'échantillon; les champs sans appui suffisant ne portent aucun appel Codex. Le mode candidate est l'union des deux volets; le consensus est leur intersection. Ces sorties portent le statut machine_predicted_unvalidated et ne sont pas des étiquettes humaines.
Scores du classifieur distillé par catégorie (deux têtes)
| Catégorie | Codex | Gemma |
|---|---|---|
| Métarecherche | 0,000 | 0,000 |
| Méta-épidémiologie (sens strict) | 0,000 | 0,000 |
| Méta-épidémiologie (sens large) | 0,000 | 0,000 |
| Bibliométrie | 0,000 | 0,000 |
| Études des sciences et des technologies | 0,000 | 0,000 |
| Communication savante | 0,000 | 0,000 |
| Science ouverte | 0,000 | 0,000 |
| Intégrité de la recherche | 0,000 | 0,000 |
| Charge utile insuffisante (le modèle a refusé de juger) | 0,002 | 0,000 |
Scores machine (provisoires)
Les deux têtes enseignantes du modèle étudiant, lues sur ce travail. Un score ordonne la base pour la relecture; il n'affirme jamais une catégorie, et le statut de validation accompagne chaque rangée tel quel.
Scores de référence d'un modèle non mature (critères de maturité non atteints, 7 itérations). Un score ordonne; il n'affirme jamais une catégorie.
score_only:v0-immature-baseline · tel quel depuis la passe de notation : score_only signifie que le nombre peut ordonner les travaux, et qu'aucune étiquette de catégorie n'en découleClassification
machine, non validéePrédiction automatique; un appel candidat d’une seule source (Gemma direct ou Codex distillé), pas un consensus.
Le détail, modèle par modèle et score par score, se trouve en fin de page sous « Comment cette classification a été obtenue ».