Adamantane-Quinoxalone Hybrids: Precision Chemotypes and Their Molecular Mechanisms in Acute Myeloid Leukemia
Acute myeloid leukemia (AML) is an aggressive blood cancer with poor prognosis, particularly when diagnosed late. Approximately 10–15% of AML cases are linked to a specific chromosomal abnormality, t(8;21), which drives the rapid proliferation of myeloid cells and contributes to disease onset. Despite advances in understanding AML biology and treatment protocols, clinical outcome for t(8;21) AML has not improved. Most patients with this subtype continue to receive standard, non-specific chemotherapies used for other AML subtypes. This one-size-fits-all approach harms both cancerous and healthy cells, emphasizing the urgent need for targeted therapies. In this study, we report the discovery of a precision chemotypes based on a quinoxalone-tethered adamantane framework. Developed using a metal- and light-free protocol, the compound selectively inhibits the proliferation of t(8;21) AML cells and induce cell death by disrupting growth and metabolic pathways, as demonstrated through bioassays, RNA sequencing, and proteomic analysis. Importantly, the compound spares other leukemic and solid cancer cells, demonstrating its specificity and potential as a precision therapy for t(8;21) AML. Overall design: Transcriptional profiling was performed in Kasumi-1 cell line. Kasumi-1 cell lines were treated at its  IC50 dose with 3j  for 24 hours and untreated control was also maintained.