Reference Detail

Ref Type

Journal Article

PMID

(39259562)

Authors

Gollner A, Rudolph D, Weyer-Czernilofsky U, Baumgartinger R, Jung P, Weinstabl H, Ramharter J, Grempler R, Quant J, Rinnenthal J, Pérez Pitarch A, Golubovic B, Gerlach D, Bader G, Wetzel K, Otto S, Mandl C, Boehmelt G, McConnell DB, Kraut N, Sini P

Title

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

Journal	Vol	Issue	Date	Pages	Journal Short Title
Molecular cancer therapeutics			2024 Sep 11		Mol Cancer Ther

URL

Abstract Text

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.

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Molecular Profile	Treatment Approach

Gene Name	Source	Synonyms	Protein Domains	Gene Description	Gene Role

Therapy Name	Drugs	Efficacy Evidence	Clinical Trials

Drug Name	Trade Name	Synonyms	Drug Classes	Drug Description

Gene	Variant	Impact	Protein Effect	Variant Description	Associated with drug Resistance

Molecular Profile	Indication/Tumor Type	Response Type	Therapy Name	Approval Status	Evidence Type	Efficacy Evidence	References
TP53 wild-type	liposarcoma	sensitive	BI 907828	Preclinical - Cell culture	Actionable	In a preclinical study, BI 907828 inhibited viability of TP53 wild-type liposarcoma cell lines in culture (PMID: 39259562).	39259562
TP53 wild-type	renal cell carcinoma	sensitive	BI 907828	Preclinical - Cell culture	Actionable	In a preclinical study, BI 907828 inhibited viability of TP53 wild-type renal cell carcinoma cell lines in culture (PMID: 39259562).	39259562
TP53 wild-type	melanoma	sensitive	BI 907828	Preclinical - Cell culture	Actionable	In a preclinical study, BI 907828 inhibited viability of TP53 wild-type melanoma cell lines in culture (PMID: 39259562).	39259562