Abstract A012: Discovery and characterization of Casdatifan (AB521), a clinical-stage, potent, and selective Hypoxia-Inducible Factor (HIF)-2α inhibitor
Notice bibliographique
Résumé
Abstract Introduction. The microenvironment of solid tumors is known to be hypoxic and requires induction of genes associated with metabolism, growth, proliferation, angiogenesis, and erythropoiesis for tumor cells to survive and metastasize. Hypoxia-inducible factors (HIFs) are the central driving force for the cellular response to hypoxia and regulate a vast array of these genes. HIF-2α protein levels are tightly regulated post-translationally in an oxygen-dependent manner. Hypoxic conditions or aberrations in the Von-Hippel Lindau (VHL) ubiquitin ligase complex lead to HIF-2α stabilization and transcription of various pro-tumorigenic gene sets. The inhibition of HIF-2α has been demonstrated to be an effective strategy to mitigate tumor growth in the clinic with the recent approval of belzutifan for the treatment of advanced metastatic clear cell renal cell carcinoma (ccRCC). However, belzutifan suffers from saturated drug exposure and peripheral PD effects at its approved dose regimen, casting uncertainty whether optimal intra-tumoral inhibition of HIF-2α was achieved in these studies. Herein, we present the discovery and characterization of casdatifan, a potent and selective small molecule HIF-2α inhibitor, with pharmacokinetic properties optimized to enable deeper PD effects and robust intra-tumoral HIF-2α inhibition. Methods. Applying a pharmacophore mapping and structure-based design approach, we identified multiple novel series of small molecule HIF-2α inhibitors. Interrogation of structure activity relationships and pharmacokinetic trends culminated in the discovery of casdatifan. The potency of casdatifan was evaluated using a suite of biochemical and cell-based assays. Efficacy and pharmacodynamic markers were also evaluated in mice bearing established A498 and 786-O ccRCC xenograft tumors treated with casdatifan. Results. Casdatifan was found to avidly bind the HIF-2α PAS-B domain and potently block HIF-2α-mediated gene transcription under physiologically relevant conditions. Additionally, robust antitumor activity was observed in mouse ccRCC xenograft models following oral administration of casdatifan. Casdatifan exhibits a favorable preclinical pharmacokinetic (PK) profile. In healthy volunteers (ARC-14, NCT05117554), casdatifan showed a favorable PK profile featuring a terminal half-life of 18-24 hours. No evidence of saturable drug absorption has been observed, with dose-proportional increase in exposure across the evaluated dose range. Potent HIF-2α inhibition is demonstrated by dose-dependent reductions in serum EPO, an established peripheral PD marker for HIF-2α inhibition. Conclusions. Extensive optimization of a novel series of HIF-2α inhibitors culminated in the discovery of casdatifan. The PK/PD profile for casdatifan is consistent with a potential best-in-class HIF-2α inhibitor, with deeper reductions of peripheral biomarkers than has been reported by clinical competition. Continued evaluation of casdatifan in patients with ccRCC and other advanced solid tumors is underway (ARC-20, NCT05536141). Citation Format: Kenneth V. Lawson, Artur Mailyan, Guillaume Mata, Joel W. Beatty, Samuel L. Drew, Jeremy T. A. Fournier, Jaroslaw Kalisiak, Ahn T. Tran, Kai Yu, Brandon R. Rosen, Clayton Hardman, Matthew Epplin, Kelsey E. Sivick, Dana Piovesan, Suan Liu, Elain Ginn, Cesar A. Meleza, Lisa Seitz, Tzuling Cheng, Amber Pham, Mohammad Ghasemi, Paul G. Foster, Matthew J. Walters, Manmohan Leleti, Jay P. Powers. Discovery and characterization of Casdatifan (AB521), a clinical-stage, potent, and selective Hypoxia-Inducible Factor (HIF)-2α inhibitor [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Optimizing Therapeutic Efficacy and Tolerability through Cancer Chemistry; 2024 Dec 9-11; Toronto, Ontario, Canada. Philadelphia (PA): AACR; Mol Cancer Ther 2024;23(12_Suppl):Abstract nr A012.
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 distillée sur la base complète
Imitation des enseignantsNi prévalence calibrée, ni vérité terrain. Validation humaine à venir. Apprise à partir de 10 348 étiquettes directes de Codex et de 10 348 étiquettes directes de Gemma. Le mode candidate est l'union des têtes enseignantes seuillées; le consensus est leur intersection. Ces sorties portent le statut machine_predicted_unvalidated et ne sont ni des étiquettes humaines ni des étiquettes directes de modèles de pointe.
Scores Codex et Gemma par catégorie
| 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) | 0,000 | 0,000 |
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 tête enseignante, 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 ».