Abstract 5479: Discovery and evaluation of GT19630, a c-Myc/GSPT1 cereblon E3 ligase modulator (CELMoD), for targeting Myc-driven blood cancers and small cell lung cancers (SCLC)
Notice bibliographique
Résumé
Abstract c-Myc is an oncogenic transcriptional factor driving tumor initiation, progression and poor prognosis in 80% of all tumor types, especially in B-cell malignancies and small cell lung cancer (SCLC) with Myc genomic alterations. Myc dysregulation have been directly linked to the poor clinical outcome in these cancers. Therefore, it is highly warranted to discover and develop novel Myc therapeutical agents for targeting Myc driven cancers. Here we described GT19630, a GSPT1/Myc CELMoD. GT19630 was discovered through an SAR effort for c-Myc degrader by using c-Myc ELISA and Western blot assays in c-Myc driven HL60 AML cells. GT19630 selectively degraded c-Myc proteins in HL60 cells (IC50=1.5 nM) as compared to growth-factor regulated c-Myc erythroid progenitor cells (TF-1 cells) with IC50=52.5 nM. GT19630 also selectively inhibited HL60 cell proliferation (IC50= 0.33 nM), as compared to its IC50 (26.2 nM) in GM-CSF-TF-1 proliferation, as well as in bone marrow colony-forming cell assays (myeloid=40.2 nM), suggesting>100X selectivity for HL60 cells over normal blood cells. Through the SAR for Myc degrader, GT19630 has been evolved as a leading molecule sharing chemical properties to CELMoDs. Therefore, this compound was further evaluated by proteomics and western blot, GT19630 was confirmed to selective degradation of CELMoD targets, GSPT1/GSPT2 (translation termination factor G1 to S phase transition proteins 1 and 2) with IC90<1 nM and CK1 alpha (IC90<10 nM), but not IKZF1/Ikaros. In silico modeling of GT19630 was performed in the DDB1−CRBN−CC-885−GSPT1 complex and confirmed the docking similarity with CELMoDs. Further, GT19630 inhibited the cell proliferation with IC50<10 nM in 74% B-cell malignant cell lines (20/27) bearing deregulated c-Myc and in 79% of SCLC cell lines (4/19) carrying deregulated Myc (c-Myc, N-Myc or L-Myc) tested. Moreover, GT19630 completely degraded Myc proteins in AML, lymphoma and multiple myeloma (c-Myc) and SCLC (c-Myc and N-Myc) xenograft tumors at the lowest dose of 1.0 mg/kg and induced complete tumor regression (lowest dose=0.3 mg/kg) tested. Furthermore, this compound eradicated lymphoma cells in Daudi-induced liquid lymphoma mouse models. In addition, GT19630, as a potent GSPT1/Myc CELMoD, demonstrated an even-driven pharmacology in vivo and induced complete tumor regression with a dosing regimen of 3 day on/7 day off. Remarkably, GT19630 selectively degraded Myc proteins in HL60 and DMS114 SCLC xenograft tumors as compared to a much less potency at degrading c-Myc in rat spleen. Finally, GT19630 demonstrated favorable PK and safety profiles (an 8-fold safety therapeutic windows) with no effect on myeloid lineages in rats at the dose of 6 mg/kg for 14 days, indicating GT19630 lacks myelosuppression as reported for other CELMoDs. Currently, GT19630 has been advanced into IND enabling stage. Citation Format: Liandong Ma, Youzhi Tong, Zhaohui Yang, Qianxiang Zhou, Hongha Yan, Ru Xu, Jie Chen, Jie Pan, Huiyuan Wang, Jiangwei Li, Dong Chen, Xiang Cai, Jie Qu, Yini Wang, Jun Qin, Yuki Nishida, Michael Andreeff, Qilnli Guo, Yuki Nishida, Michael Andreeff. Discovery and evaluation of GT19630, a c-Myc/GSPT1 cereblon E3 ligase modulator (CELMoD), for targeting Myc-driven blood cancers and small cell lung cancers (SCLC) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5479.
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 | 0,001 |
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 ».