Abstract B236: A small molecule disrupts the BCL6 transcriptional repressor complex and kills lymphoma cells <i>in vitro</i> and <i>in vivo</i>
Notice bibliographique
Résumé
Abstract The BCL6 transcriptional repressor is the most frequently involved oncogene in diffuse large B-cell lymphoma (DLBCL) and is also implicated in solid tumors. BCL6 depletion by siRNA or BCL6 blockade using peptide inhibitors kills DLBCL cells, demonstrating that lymphoma cells are addicted to BCL6. Based on these data we hypothesized that BCL6 could serve as an excellent therapeutic target in lymphomas and other cancers. From the mechanistic standpoint BCL6 mediates transcriptional repression through recruitment of the SMRT, N-CoR and BCOR corepressors to a lateral groove motif on its BTB domain. Our crystallographic, biochemical, and functional studies suggested that a particular section of the BTB lateral groove was amenable to development of small molecule inhibitors. Since these residues are unique to BCL6 and no other BTB proteins we predicted that molecules designed to bind to this region would be specific. To identify such molecules we performed a computer-aided drug design (CADD) screen of over 1,000,000 compounds. After two rounds of docking with increasing stringency, target flexibility simulation and chemical diversity clustering, we generated a priority list of compounds likely to bind the BCL6 BTB lateral groove. A number of these compounds indeed blocked the BCL6 - corepressor interaction and inhibited the transcriptional repressor function of BCL6. Analogs of the 10 leading compounds were subjected to biological testing. One of these families, the 79 series, was selected for further study because this group contained the largest number of active compounds. X-ray crystallography of the most active 79 family compound, called 79-6, confirmed binding to the critical BTB lateral groove region. 79-6 penetrated and accumulated in intact lymphoma cells as determined by HPLC-MS. 79-6 blocked the repressor activity of BCL6 but not other BTB proteins, blocked the recruitment of corepressors to endogenous BCL6 target genes as shown by ChIP, and induced the re-expression of BCL6 target genes in BCL6-positive (but not BCL6 negative) lymphoma cells as shown by q-PCR. Most importantly, 79-6 killed BCL6-positive lymphoma cells by apoptosis induction but had no effect on BCL6-negative lymphoma cells. Extensive toxicological studies performed in C57/BL mice revealed no toxic effects (by complete serum chemistry, CBC, histopathological examination of every organ including bone marrow, etc). Pharmacokinetic analysis (by HPLC-MS/MS) in SCID mice showed that 79-6 penetrates and accumulates in tumors after intraperitoneal administration. 79-6 potently inhibited the growth of established human BCL6-positive xenografts (Ly7 and SUDHL6) but not of BCL6-negative tumors (Toledo), again without toxicity to other organs. The compound also killed primary BCL6-positive DLBCL explants from human patients. 79-6 is currently being optimized for used in humans. These results demonstrate that therapeutic chemical manipulation of transcriptional repression via modulation of protein-protein interactions is a viable option for development of potent and non-toxic anti-cancer drugs. Citation Information: Mol Cancer Ther 2009;8(12 Suppl):B236.
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 | 0,001 |
| Charge utile insuffisante (le modèle a refusé de juger) | 0,004 | 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 ».