Abstract 1292: A new generation of N-terminal domain androgen receptor inhibitors, with improved pharmaceutical properties, in castration-resistant prostate cancer models
Notice bibliographique
Résumé
Abstract Introduction: The androgen receptor (AR) pathway continues to drive castration-resistant prostate cancer (CRPC) even in late stages of the disease, and ligand binding domain (LBD)-linked resistance inevitably emerges. Selective inhibition of the N-terminal domain (NTD) of the AR can inhibit its’ 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. A new generation of NTD transcriptional inhibitors (Anitens) has been generated. Examples of this new class, EPI-7170 and EPI-7245, demonstrate improved potency, metabolic stability and pharmaceutical properties, and are potent against anti-androgen resistant prostate cancers in in vitro and in preclinical models. Methods: Chemical structure activity relationships were developed to identify more potent molecules as measured by both 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 were also optimized using a variety of cellular experiments. Results: These next generation Anitens demonstrated a 10-20-fold improvement on AR-driven cellular potency, with IC50’s of 0.5-1 uM compared to 10 uM for EPI-002. Aniten AR inhibition was specific to the NTD, as demonstrated by the absence of LBD binding and the inhibition of the AR-V7-driven transcription inLNCaP95 model. In vitro proliferation assays demonstrated AR-dependent activity, with an IC50 ~ 1 uM in LNCaP and >10 uM in the AR-independent cell model PC-3. The antiproliferative effect aligned with the inhibitory effect on a subset of AR-driven genes. In vivo, next generation Anitens demonstrated PSA serum decreases along with significant tumor growth inhibition in mice bearing LNCaP tumors. While EPI-7170 represents a major advance, subsequent chemistry efforts led to the generation of EPI-7245 and other next generation Anitens which exhibit IC50’s <500 nM. These new compounds exhibited favorable ADME and PK profiles, with half-life ~ 8 hrs in mice, and predicted low human clearance. Conclusions: Promising next-generation Aniten compounds have been identified which retain the NTD specificity of first-generation agents. These new molecules demonstrate major improvements in potency and metabolic stability in comparison to the first-generation clinical compound EPI-002. These next generation Anitens, by selectively inhibiting AR transcription in both hormone sensitive and castrated resistant prostate cancer, represent an important next step in AR targeted therapeutics. Citation Format: Ronan Le Moigne, Nasrin R. Mawji, C. Adriana Banuelos, Jun Wang, Kunzhong Jian, Raymond J. Andersen, Marianne D. Sadar, Han-Jie Zhou, Peter Virsik. A new generation of N-terminal domain androgen receptor inhibitors, with improved pharmaceutical properties, in castration-resistant prostate cancer models [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 1292.
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) | 0,002 | 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 ».