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

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 M...