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

• DOI: 10.1158/1535-7163.c.7567711
• Publication Date: 2024-12-03T08:21:59Z
• Authors: Andreas Gollner; Dorothea Rudolph; Ulrike Weyer-Czer...; Rosa Baumgartinger; Peter Jung; Harald Weinstabl; Jürgen Ramharter; Rolf Grempler; Jens Quant; Jörg Rinnenthal; Alejandro Pérez P...; Bojana Golubovic; Daniel Gerlach; Gerd Bader; Kristiane Wetzel; Sebastian Otto; Christian Mandl; Guido Boehmelt; Darryl B. McConnell; Norbert Kraut; Patrizia Sini

<div>Abstract<p>p53 is known as the guardian of genome and one most important tumor suppressors. It inactivated in tumors, either via protein p53 (<i>TP53</i>) gene mutation or copy number amplification key negative regulators, e.g., mouse double minute 2 (<i>MDM2</i>). Compounds that bind to MDM2 disrupt its interaction with restore suppressor activity, thereby promoting cell cycle arrest apoptosis. Previous clinical experience MDM2–p53 protein–protein antagonists (MDM2–p53 antagonists) has demonstrated thrombocytopenia neutropenia represent on-target dose-limiting toxicities might restrict their therapeutic utility. Dosing less frequently, while maintaining efficacious exposure, represents an approach mitigate toxicity improve window antagonists. However, achieve this, a molecule possessing excellent potency ideal pharmacokinetic properties required. Here, we present discovery characterization brigimadlin (BI 907828), novel, investigational spiro-oxindole antagonist. Brigimadlin exhibited high bioavailability well dose-linear pharmacokinetics preclinical models. treatment restored activity led apoptosis induction models <i>TP53</i> wild-type, <i>MDM2</i>-amplified cancer. Oral administration intermittent dosing schedule induced potent growth inhibition several xenograft Exploratory studies (NCT03449381) showed systemic exposure long plasma elimination half-life patients cancer who received oral brigimadlin. These findings support continued evaluation cancers, such dedifferentiated liposarcoma.</p></div>