MP34-04 A NEW GENERATION OF N-TERMINAL DOMAIN ANDROGEN RECEPTOR INHIBITORS IN CASTRATION-RESISTANT PROSTATE CANCER MODELS
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Résumé
You have accessJournal of UrologyProstate Cancer: Advanced (including Drug Therapy) IV (MP34)1 Apr 2019MP34-04 A NEW GENERATION OF N-TERMINAL DOMAIN ANDROGEN RECEPTOR INHIBITORS IN CASTRATION-RESISTANT PROSTATE CANCER MODELS Ronan Le Moigne*, Han-Jie Zhou, Nasrin R. Mawji, C. Adriana Banuelos, Jun Wang, Kunzhong Jian, Peter Virsik, Raymond J. Andersen, and Marianne D. Sadar Ronan Le Moigne*Ronan Le Moigne* More articles by this author , Han-Jie ZhouHan-Jie Zhou More articles by this author , Nasrin R. MawjiNasrin R. Mawji More articles by this author , C. Adriana BanuelosC. Adriana Banuelos More articles by this author , Jun WangJun Wang More articles by this author , Kunzhong JianKunzhong Jian More articles by this author , Peter VirsikPeter Virsik More articles by this author , Raymond J. AndersenRaymond J. Andersen More articles by this author , and Marianne D. SadarMarianne D. Sadar More articles by this author View All Author Informationhttps://doi.org/10.1097/01.JU.0000555947.83770.aaAboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVES: The androgen receptor (AR) pathway continues to drive castration-resistant prostate cancer (CRPC) even in late stages of the disease. While the latest generation anti-androgens provide clinical benefits to CRPC patients, resistance linked with the ligand binding domain (LBD) inevitably emerges. Selective inhibition of the N-terminal domain (NTD) of the AR can inhibit AR transcription even in the presence of anti-androgen resistance. A Phase I clinical trial of the first generation AR NTD inhibitor, EPI-506 (EPI-002 pro-drug), demonstrated PSA declines in anti-androgen resistant metastatic CRPC patients. However, these declines were minor and of short duration, revealing the need for more potent and metabolically stable NTD inhibitors. Next generation NTD inhibitors (anitens) have been developed and their characterization will be presented. METHODS: Chemical structure activity relationships were developed in order to increase molecule potency in cellular and in vivo assays, while metabolic stability improvements were assessed in in vitro ADME assays and in animal pharmacokinetic studies. In addition, the on-target activity and selectivity was also optimized using a variety of cellular experiments. RESULTS: Next generation anitens, EPI-7170, EPI-7245 and EPI-7324, demonstrated a 10-70 fold improvement on AR-driven cellular potency when compared to the clinical compound EPI-002. While IC50s ranged from <500 nM and ∼1 uM, for EPI-7245 and EPI-7170 respectively, EPI-7324 diplayed potency <300 nM, similar to enzalutamide and bicalutamide. In vitro proliferation assays demonstrated on-target activity for these next-generation anitens, with an IC50 >5 fold higher in AR-independent PC-3 cells compared to AR-dependant LNCaP cells while also displaying activity in AR-V7-driven cellular models. While EPI-7170 exhibited ∼ 70% tumor growth inhibition in castrated mice bearing LNCaP tumors, its ADME and PK profile were not optimal. More recent molecules, including EPI-7245 and EPI-7324, represent next generation aniten molecules with improved potency, selectivity, and metabolic stability compared to EPI-002 and EPI-7170. CONCLUSIONS: The next generation aniten compounds are 10-70 times more active than EPI-002 in cellular potency assays, predicted to be metabolically stable, and selectively inhibit AR transcription in anti-androgen resistant models. Their potential in overcoming anti-androgen clinical resistance to the current generation of anti-androgens will be discussed. Source of Funding: The work was funded by ESSA pharma Houston, TX; Vancouver, Canada; Houston, TX; Vancouver, Canada© 2019 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 201Issue Supplement 4April 2019Page: e496-e497 Advertisement Copyright & Permissions© 2019 by American Urological Association Education and Research, Inc.MetricsAuthor Information Ronan Le Moigne* More articles by this author Han-Jie Zhou More articles by this author Nasrin R. Mawji More articles by this author C. Adriana Banuelos More articles by this author Jun Wang More articles by this author Kunzhong Jian More articles by this author Peter Virsik More articles by this author Raymond J. Andersen More articles by this author Marianne D. Sadar More articles by this author Expand All Advertisement PDF downloadLoading ...
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 | 0,001 |
| Bibliométrie | 0,001 | 0,001 |
| Études des sciences et des technologies | 0,000 | 0,000 |
| Communication savante | 0,001 | 0,001 |
| Science ouverte | 0,001 | 0,000 |
| Intégrité de la recherche | 0,001 | 0,002 |
| Charge utile insuffisante (le modèle a refusé de juger) | 0,037 | 0,011 |
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 ».