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

• Published in: Molecular cancer therapeutics Vol. 23; no. 12; pp. 1689 - OF14
• Main Authors: Gollner, Andreas, Rudolph, Dorothea, Weyer-Czernilofsky, Ulrike, Baumgartinger, Rosa, Jung, Peter, Weinstabl, Harald, Ramharter, Jürgen, Grempler, Rolf, Quant, Jens, Rinnenthal, Jörg, Pérez Pitarch, Alejandro, Golubovic, Bojana, Gerlach, Daniel, Bader, Gerd, Wetzel, Kristiane, Otto, Sebastian, Mandl, Christian, Boehmelt, Guido, McConnell, Darryl B, Kraut, Norbert, Sini, Patrizia
• Format: Journal Article
• Language: English
• Published: United States American Association for Cancer Research 03.12.2024
• Subjects: Animals; Antineoplastic Agents - administration & dosage; Antineoplastic Agents - pharmacokinetics; Antineoplastic Agents - pharmacology; Antineoplastic Agents - therapeutic use; Apoptosis - drug effects; Cell Line, Tumor; Cell Proliferation - drug effects; Drug Discovery; Drug Mechanisms; Female; First Disclosures; Humans; Indoles - administration & dosage; Indoles - pharmacokinetics; Indoles - pharmacology; Male; Mice; Proto-Oncogene Proteins c-mdm2 - antagonists & inhibitors; Rats; Small Molecule Agents; Spiro Compounds - administration & dosage; Spiro Compounds - pharmacokinetics; Spiro Compounds - pharmacology; Translational Research; Tumor Suppressor Protein p53 - genetics; Tumor Suppressor Protein p53 - metabolism; Xenograft Model Antitumor Assays
• ISSN: 1535-7163; 1538-8514; 1538-8514
• DOI: 10.1158/1535-7163.MCT-23-0783

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.