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

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)

Kaynakça

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