PSMB8 as a Novel Target for AML Therapy: Uncovering Synergistic Potential with PI3K Inhibitors

Authors : Onur Ates, Yağmur Kiraz

Pages : 64-72

Doi:10.7240/jeps.1638390

View : 43 | Download : 55

Publication Date : 2025-03-25

Article Type : Research Paper

Abstract :Acute myeloid leukemia (AML) is a bone marrow condition that arises from abnormalities in hematopoietic stem cells due to genetic mutations in progenitor blood cells. These mutations lead to the uncontrolled proliferation of malignant clonal myeloid stem cells. Although extramedullary symptoms such as myeloid sarcomas and leukemia cutis can arise, the main issue continues to be the disturbances in hematologic cell production. Despite the high complete remission rate in elderly patients, a notable number of patients experience relapse within three years. To address this issue, new objectives must be identified. In a previous study, PSMB8 drew our attention due to its elevated expression levels in AML patients exhibiting lower survival rates compared to those with reduced expression levels. PSMB8 was used for drug repurposing studies by performing in silico drug screening, an ADMET analysis which is followed by Molecular Dynamics (MD) simulations. Three ligand molecules were identified as potential treatment options for AML which were Adozelesin, Fiduxosin and Omipalisib. Omipalisib is known as a PI3K/mTOR inhibitor which was taken our attention for cytotoxic analysis due to overexpression of PI3K/mTOR pathway proteins in AML development. In the subsequent phase, we assessed the cytotoxicity of Omipalisib in comparison to ONX-0914, an inhibitor of PSMB8, in the HL60 cell lines. This research indicated that PSMB8 could be a possible target for Acute Myeloid Leukemia and that a potential medication can be utilized for targeted treatment.
Keywords : Omipalisib, ONX-0914, AML PI3K/mTOR, PSMB8, Proteazom