Abstract 3829: NEO1132 and NEO2734, novel dual bromodomain inhibitors of both BET and CREBBP/EP300, compared to single BET or CREBB/EP300 inhibitors in diffuse large B cell lymphoma
Notice bibliographique
Résumé
Abstract Lymphoma cells have frequent deregulation of their epigenome. The Bromodomain (BRD) and Extra-Terminal domain (BET) proteins are key regulators of the transcription process. The acetyltransferases cyclic AMP response element binding protein (CREB)-binding protein (CBP) and the E1A interacting protein of 300 kDa (EP300) are highly homologous BRD-containing transcriptional co-activators and are often mutated in diffuse large B cell lymphoma (DLBCL). Targeting the individual classes of proteins is a new therapeutic approach, with BET inhibitors having both preclinical and early clinical anti-lymphoma activity. NEO2734 and NEO1132 are novel chemically distinct dual inhibitors of both BET and CREBBP/EP300 proteins with different affinity for their targets. Here, we present initial data exploring their anti-tumor activity in DLBCL models. Lymphoma cell lines were exposed to increasing doses of compounds for 72h followed by MTT assay. Twenty-seven DLBCL cell lines were exposed to NEO2734 and NEO1132. NEO2734 showed anti-tumor activity with a median IC50 of 157 nM (95% C.I., 135-214). While, NEO1132 showed a lower activity compared to NEO2734, with a median IC50 of 400nM (95% C.I., 316-622). For both compounds, cell lines derived from activated B-cell-like (ABC) DLBCL (n.=8) were more sensitive than those derived from germinal center B-cell (GCB) DLBCL (n.=19) (P=0.009, P=0.03 respectively). No differences were observed based on double hit MYC/BCL2 (yes, n.=6; no, n.=14), MYC (translocation: yes, n=8; no, n.=13), BCL2 (translocation: yes, n=12; no, n.=6), TP53 (inactive: yes, n=14; no, n.=6), CREBBP (mutated, n.=10; wild type, n=16), or EP300 (mutated, n.=5; wild type, n.=20) gene status. All the cell lines were also exposed to a BET inhibitor (birabresib, OTX015) (Boi et al, Clinical Cancer Res 2015) and to a CREBBP/EP300 inhibitor (CBP30) (Hammitzsch et al, PNAS 2015). The median IC50 values of the two molecules were 237 nM (95% C.I., 171-344) and 5.5 μM (95% C.I., 4.2-8.3 μM) respectively. The four compounds presented a similar pattern of anti-proliferative activity across all the cell lines (NEO2734 vs NEO1132 R2=0.98, P < 0.001; NEO2734 vs birabresib: R2=0.84, P < 0.001; NEO2734 vs CBP30, R2 = 0.73, P < 0.001; birabresib vs CBP30, R2 = 0.73, P < 0.001) but with different degrees of IC50. NEO2734 was significantly more potent than birabresib (P=0.0182), CBP30 (P<0.001) and NEO1132 (P<0.001). The higher activity of NEO2734 compared to NEO1132 may be attributable to its superior potency in binding CREBBP and EP300, confirming the importance of the BET/CREBBP/EP300 simultaneous inhibition. The novel dual BET and CREBBP/EP300 inhibitors NEO2734 and NEO1132 showed potent in vitro anti-tumor activity across a large panel of DLBCL cell lines and their activity appear to be proportional to the binding affinity for both BET and CREBBP/EP300 proteins. Citation Format: Filippo Spriano, Eugenio Gaudio, Chiara Tarantelli, Gaetanina Golino, Luciano Cascione, Emanuele Zucca, Anastasios Stathis, Francis Giles, Francesco Bertoni. NEO1132 and NEO2734, novel dual bromodomain inhibitors of both BET and CREBBP/EP300, compared to single BET or CREBB/EP300 inhibitors in diffuse large B cell lymphoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3829.
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) | 0,003 | 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 ».