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Structural modification of clinically successful kinase inhibitors represents a promising approach for discovering novel anti-leukemic agents with improved biological activities. In the present study, we investigated the anti-leukemic activity and mechanism of action of MO2455, a newly synthesized imatinib-derived compound, in monocytic leukemia U937, THP\u22121, and T-cell leukemia CCRF-CEM cells. MO2455 showed substantial cytotoxic activity against all three cell lines, with IC50 values of 0.83 \u03bcM, 0.43 \u03bcM, and 0.57 \u03bcM in U937, THP\u22121, and CCRF-CEM cells, respectively. Treatment with MO2455 induced early mitochondrial membrane depolarization, internucleosomal DNA laddering, a significant accumulation of sub\u2212G1 population and increased Annexin V positivity, suggesting typical apoptosis without cell cycle arrest in U937 cells. MO2455 induced \u03b3-H2AX induction and upregulated the pro-apoptotic NOXA and BBC3 genes. THP\u22121 and CCRF-CEM cells displayed distinct large DNA fragmentation with smearing. In PBMCs from two healthy donors, IC50 values were 0.99 and 0.60 \u03bcM, respectively, although the cells remained morphologically healthy without obvious extensive cell death. Overall, MO2455 exhibits substantial anti-leukemic activity and induces cell death through apoptosis and other mechanisms, supporting further investigation as an anti-leukemic agent.<\/jats:p>","DOI":"10.3390\/cells15191780","type":"journal-article","created":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T08:17:27Z","timestamp":1790756247000},"page":"1780","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Cell Death Induction by MO2455, a Novel Potential Anti-Cancer Agent in Monocytic and T-Cell Leukemia Cells"],"prefix":"10.3390","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4136-6909","authenticated-orcid":false,"given":"Ankitha","family":"Vadi Velu","sequence":"first","affiliation":[{"name":"Department of Molecular and Genomic Biomedicine, Center for Bioinformatics and Molecular Medicine, Graduate School of Biomedical Sciences, Nagasaki University, Nagasaki 852-8523, 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