8PWC
Crystal structure of MDM2 with Brigimadlin
Summary for 8PWC
| Entry DOI | 10.2210/pdb8pwc/pdb |
| Descriptor | E3 ubiquitin-protein ligase Mdm2, Brigimadlin (3 entities in total) |
| Functional Keywords | inhibitor, complex, ligase |
| Biological source | Homo sapiens (human) |
| Total number of polymer chains | 3 |
| Total formula weight | 39551.58 |
| Authors | |
| Primary citation | Gollner, A.,Rudolph, D.,Weyer-Czernilofsky, U.,Baumgartinger, R.,Jung, P.,Weinstabl, H.,Ramharter, J.,Grempler, R.,Quant, J.,Rinnenthal, J.,Perez Pitarch, A.,Golubovic, B.,Gerlach, D.,Bader, G.,Wetzel, K.,Otto, S.,Mandl, C.,Boehmelt, G.,McConnell, D.B.,Kraut, N.,Sini, P. Discovery and Characterization of Brigimadlin, a Novel and Highly Potent MDM2-p53 Antagonist Suitable for Intermittent Dose Schedules. Mol.Cancer Ther., 2024 Cited by PubMed Abstract: 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) have 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 cancer patients who received oral brigimadlin. These findings support the continued clinical evaluation of brigimadlin in patients with MDM2-amplified cancers, such as dedifferentiated liposarcoma. PubMed: 39259562DOI: 10.1158/1535-7163.MCT-23-0783 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (1.461 Å) |
Structure validation
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