Discovery and Characterization of Brigimadlin, a Novel and Highly Potent MDM2-p53 Antagonist Suitable for Intermittent Dose Schedules.

Autor:	Gollner A; Boehringer Ingelheim RCV GmbH & Co. KG, Vienna, Austria., Rudolph D; Boehringer Ingelheim RCV GmbH & Co. KG, Vienna, Austria., Weyer-Czernilofsky U; Boehringer Ingelheim RCV GmbH & Co. KG, Vienna, Austria., Baumgartinger R; Boehringer Ingelheim RCV GmbH & Co. KG, Vienna, Austria., Jung P; Boehringer Ingelheim RCV GmbH & Co. KG, Vienna, Austria., Weinstabl H; Boehringer Ingelheim RCV GmbH & Co. KG, Vienna, Austria., Ramharter J; Boehringer Ingelheim RCV GmbH & Co. KG, Vienna, Austria., Grempler R; Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, Connecticut., Quant J; Boehringer Ingelheim RCV GmbH & Co. KG, Vienna, Austria., Rinnenthal J; Boehringer Ingelheim RCV GmbH & Co. KG, Vienna, Austria., Pérez Pitarch A; Boehringer Ingelheim Pharma GmbH & Co. KG, Ingelheim am Rhein, Germany., Golubovic B; Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach an der Riss, Germany., Gerlach D; Boehringer Ingelheim RCV GmbH & Co. KG, Vienna, Austria., Bader G; Boehringer Ingelheim RCV GmbH & Co. KG, Vienna, Austria., Wetzel K; Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach an der Riss, Germany., Otto S; Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach an der Riss, Germany., Mandl C; Boehringer Ingelheim RCV GmbH & Co. KG, Vienna, Austria., Boehmelt G; Boehringer Ingelheim RCV GmbH & Co. KG, Vienna, Austria., McConnell DB; Boehringer Ingelheim RCV GmbH & Co. KG, Vienna, Austria., Kraut N; Boehringer Ingelheim RCV GmbH & Co. KG, Vienna, Austria., Sini P; Boehringer Ingelheim RCV GmbH & Co. KG, Vienna, Austria.
Jazyk:	angličtina
Zdroj:	Molecular cancer therapeutics [Mol Cancer Ther] 2024 Dec 03; Vol. 23 (12), pp. 1689-1702.
DOI:	10.1158/1535-7163.MCT-23-0783
Abstrakt:	p53 is known as the guardian of the genome and is one of the most important tumor suppressors. It is inactivated in most tumors, either via tumor protein p53 (TP53) gene mutation or copy number amplification of key negative regulators, e.g., mouse double minute 2 (MDM2). Compounds that bind to the MDM2 protein and disrupt its interaction with p53 restore p53 tumor suppressor activity, thereby promoting cell cycle arrest and apoptosis. Previous clinical experience with MDM2-p53 protein-protein interaction antagonists (MDM2-p53 antagonists) has demonstrated that thrombocytopenia and neutropenia represent on-target dose-limiting toxicities that might restrict their therapeutic utility. Dosing less frequently, while maintaining efficacious exposure, represents an approach to mitigate toxicity and improve the therapeutic window of MDM2-p53 antagonists. However, to achieve this, a molecule possessing excellent potency and ideal pharmacokinetic properties is required. Here, we present the discovery and characterization of brigimadlin (BI 907828), a novel, investigational spiro-oxindole MDM2-p53 antagonist. Brigimadlin exhibited high bioavailability and exposure, as well as dose-linear pharmacokinetics in preclinical models. Brigimadlin treatment restored p53 activity and led to apoptosis induction in preclinical models of TP53 wild-type, MDM2-amplified cancer. Oral administration of brigimadlin in an intermittent dosing schedule induced potent tumor growth inhibition in several TP53 wild-type, MDM2-amplified xenograft models. Exploratory clinical pharmacokinetic studies (NCT03449381) showed high systemic exposure and a long plasma elimination half-life in patients with cancer who received oral brigimadlin. These findings support the continued clinical evaluation of brigimadlin in patients with MDM2-amplified cancers, such as dedifferentiated liposarcoma. (©2024 The Authors; Published by the American Association for Cancer Research.)
Databáze:	MEDLINE
Externí odkaz:	Zobrazit plný text záznamu