Abstract A121: Direct SH2 domain-targeting inhibitors of Stat3: Potent anticancer agents and mitigators of drug resistance.
Notice bibliographique
Résumé
Abstract As a master regulator of cell signaling and tumorigenesis, signal transducer and activator of transcription 3 (Stat3) protein has emerged at the forefront of anti-cancer drug development. Abnormal Stat3 activity has been demonstrated in a wide variety of human cancers including leukemia, lymphoma, multiple myeloma, glioblastoma and cancers of the pancreas, breast, prostate, and ovary. Constitutive Stat3 activation interferes with normal cell cycling and causes the accumulation of anti-apoptotic proteins. This renders malignant cells resistant to naturally occurring apoptotic cues and allows them subject to proliferate rapidly. Cancer cells become reliant on increased levels of Stat3 activity are vulnerable to therapeutic intervention through Stat3 inhibition. In healthy cells, Stat3 activity is transient and non-essential, thus, inhibiting Stat3 presents an avenue for the development of novel cancer therapeutic agents. Our approach involves the interruption of several critical Stat3 functions by occupation of the SH2 domain with small molecule inhibitors. Stat3's SH2 domain is a key component in the Stat3 signaling pathway as it not only facilitates activation of monomeric Stat3 but also moderates the formation of the transcriptionally active Stat3:Stat3 homodimer. Our research groups have conducted a thorough structure-activity relationship on a known Stat3-SH2 domain binder (S3I-201) and have discovered several more potent and more drug-like Stat3 inhibitors. Most recently, we have utilized a tetrapodal scaffold that has allowed more complete occupation of the SH2 domain and resulted in greatly improved binding affinity. These novel compounds effectively displace an SH2 domain-binding peptide probe, prevent Stat3 phosphorylation in cell line models and suppress Stat3 target gene expression at near-nanomolar concentrations. Our latest Stat3 inhibitors are effective across a wide variety of human cancers and exhibit a 10–20-fold improvement in cellular EC50 values over the parent compound, S3I-201. Remarkable activity is observed in mouse xenograft models of human breast cancer where nearly complete inhibition of tumor growth is observed at a dosing of 3 mg/kg daily. Furthermore, recent experiments demonstrate the same potent activity when the drug is administered by oral gavage, with plasma drug concentrations reaching 20 μM. Preliminary investigations have also shown that our lead compounds can re-sensitize malignant cells that are resistant to conventional chemotherapeutics agents. We present our newest library of Stat3 inhibitors, which holds great promise in the fight against cancer. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr A121.
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 distillée sur la base complète
Imitation des enseignantsNi prévalence calibrée, ni vérité terrain. Validation humaine à venir. Apprise à partir de 10 348 étiquettes directes de Codex et de 10 348 étiquettes directes de Gemma. Le mode candidate est l'union des têtes enseignantes seuillées; le consensus est leur intersection. Ces sorties portent le statut machine_predicted_unvalidated et ne sont ni des étiquettes humaines ni des étiquettes directes de modèles de pointe.
Scores Codex et Gemma par catégorie
| 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) | 0,000 | 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 tête enseignante, 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 ».