Preclinical Evaluation of Brigimadlin (BI 907828) As a Novel MDM2 Inhibitor in Acute Lymphoblastic Leukemia

Yıl 2025, Cilt: 8 Sayı: 5, 1450 - 1459, 15.09.2025

Erhan Aptullahoğlu

https://doi.org/10.34248/bsengineering.1696059

Öz

Acute lymphoblastic leukemia (ALL) is a genetically heterogeneous malignancy that frequently retains wild-type TP53 at diagnosis, rendering it a potential candidate for therapies targeting upstream regulators of p53 such as MDM2. Brigimadlin (BI 907828) is a next-generation, orally bioavailable MDM2-p53 antagonist with established activity in solid tumors, yet its therapeutic potential in hematologic malignancies remains underexplored. In this study, the in vitro effects of brigimadlin were investigated using a panel of ALL cell lines with a defined TP53 status. Cell viability assays demonstrated potent, dose-dependent growth inhibition in TP53 wild-type cell lines Nalm-6 and RS4;11, with low nanomolar IC₅₀ values (38 nM and 18 nM, respectively). In contrast, the TP53-mutant CCRF-CEM line displayed resistance, with minimal viability loss even at micromolar concentrations. Microscopic analysis corroborated these findings, showing marked cytotoxicity in TP53-functional cell lines but not in TP53-deficient one. Quantitative RT-PCR analysis revealed strong induction of p53 target genes, including CDKN1A, PUMA, BAX, and MDM2, in wild-type Nalm-6 cells following treatment, consistent with reactivation of p53-mediated transcriptional signature. No gene induction was observed in the TP53-mutant cell line, supporting the specificity of brigimadlin’s action. Taken together, these findings highlight brigimadlin’s potential to selectively target p53-functional ALL cells and provide foundational preclinical evidence for its continued investigation. In vivo studies in TP53 wild-type models are warranted to assess its translational relevance, and future research may explore its integration into combination regimens or biomarker-guided therapeutic strategies.

Anahtar Kelimeler

Acute lymphoblastic leukaemia , MDM2-p53 antagonists , MDM2 , p53 , Brigimadlin (BI 907828)

Etik Beyan

Ethics committee approval was not required for this study because of there was no study on animals or humans.

Destekleyen Kurum

Bilecik Şeyh Edebali University

Kaynakça

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