Abstract
Venetoclax, a chemotherapeutic agent for hematologic malignancies, faces resistance due to Myeloid Cell Leukemia-1 (MCL-1) upregulation. AMG-176, an MCL-1 inhibitor, shows promise as a therapeutic target in these malignancies. However, the serum metabolic profile following AMG-176 intervention in chronic lymphocytic leukemia (CLL) remains unexplored. This study aims to elucidate potential biomarkers and mechanisms of AMG-176 intervention in CLL. Peripheral blood mononuclear cells (PBMCs) isolated from five CLL patients were treated with varying doses of AMG-176. The IC50 value was determined using the CCK8 assay. After 24-hour intervention, cell supernatants underwent untargeted metabolomics analysis via Liquid Chromatography-Mass Spectrometry (LC-MS). Distinct metabolic profiles emerged between control, low-dose, and high-dose AMG-176 groups. Of 1,934 identified metabolites across 23 classes, six differential metabolites (L-Glutamine, L-Phenylalanine, Xanthosine, Inosine, Guanosine, and 2'-Deoxyadenosine) were enriched in multiple pathways. L-Glutamine and L-Phenylalanine, notably associated with leukemia, showed significant concentration-dependent changes with AMG-176 intervention. Key enriched pathways included metabolic pathways, ABC transporters, and amino acid biosynthesis. L-Glutamine and L-Phenylalanine emerge as potential biomarkers for AMG-176 intervention in CLL, warranting further validation in larger studies. This metabolomics-based pilot study provided a reference for the treatment of CLL and the application of AMG-176. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s12288-025-02059-y.