Abstract A25: COTI-2, a novel small molecule that is effective against multiple human cancer cell lines in vitro and in vivo
Notice bibliographique
Résumé
Abstract Introduction: Identification of novel anti-cancer compounds with high efficacy and low toxicity is critical in drug development. High-throughput screening and other such strategies are generally resource-intensive. Therefore, in silico computer-aided drug design has gained rapid acceptance and popularity. We employed our proprietary computational platform (CHEMSAS®), which uses a unique combination of traditional and modern pharmacology principles, statistical modeling, medicinal chemistry, and machine-learning technologies to discover and optimize novel compounds that could target various cancers. COTI-2 is a novel, small molecule, candidate anti-cancer drug identified using CHEMSAS. This study describes the in vitro and in vivo evaluation of COTI-2. Methods: A series of cell proliferation and cell viability assays including alamarBlue®, cell counting, CellTiter-Blue®, and flow cytometry were used to measure the effect of COTI-2 on tumor cell proliferation and apoptosis in a wide range of human cancer cell lines. COTI-2 was also tested in vivo against several human xenograft models. Two independent kinase assays were used to examine whether COTI-2 is a kinase inhibitor. The capacity of COTI-2 to inhibit Hsp90 was determined using an Hsp90 ATPase activity assay. A series of knockdown studies of the PI3K/AKTmTOR pathway were used to evaluate the effect of COTI-2 on this pathway. Finally, the effect of COTI-2 on mutant p53 was evaluated using p53 conformational studies. Results: Our data demonstrate that COTI-2 is effective against a diverse group of human cancer cell lines regardless of their tissue of origin or genetic makeup. Most treated cancer cell lines were sensitive to COTI-2 at nanomolar concentrations. When compared to traditional chemotherapy or targeted-therapy agents, COTI-2 showed superior activity against tumor cells, in vitro and in vivo. Despite its potent anti-tumor efficacy, COTI-2 was safe and well-tolerated in mouse hosts of human tumor xenografts in vivo. Our preliminary mechanism of action results indicate that COTI-2 is not a traditional kinase or an Hsp90 inhibitor but that AKT and p53 are likely targets of COTI-2. Conclusion: COTI-2 is a novel, anti-cancer agent that was designed by our proprietary computational platform CHEMSAS. It is effective against a wide variety of human cancer cell lines in vitro and in vivo, regardless of their tissue of origin or genetic make-up. COTI-2 induces apoptosis in tumor cells in vitro, is well-tolerated in vivo, and does not cause toxicity in treated animals. COTI-2 is not a traditional kinase or Hsp90 inhibitor. Finally, COTI-2 appears to target mutant p53 and the PI3K/AKT/mTOR pathway. Citation Format: Kowthar Y. Salim, Saman Maleki Vareki, Wayne R. Danter, James Koropatnick. COTI-2, a novel small molecule that is effective against multiple human cancer cell lines in vitro and in vivo. [abstract]. In: Proceedings of the AACR Precision Medicine Series: Targeting the Vulnerabilities of Cancer; May 16-19, 2016; Miami, FL. Philadelphia (PA): AACR; Clin Cancer Res 2017;23(1_Suppl):Abstract nr A25.
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) | 0,001 | 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) | 0,007 | 0,001 |
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 ».