Adamantane-Quinoxalone Hybrids: Precision Chemotypes and Their Molecular Mechanisms in Acute Myeloid Leukemia

Abstract

Acute myeloid leukemia (AML) is an aggressive blood cancer with a poor prognosis, especially when diagnosed late. Around 10-15% of cases involve the specific chromosomal abnormality t(8;21), which drives uncontrolled myeloid cell proliferation and contributes to disease onset. Despite advances in AML research and treatment protocols, outcomes for t(8;21) AML remain stagnant, as patients receive standard, nonspecific chemotherapies. This one-size-fits-all approach targets both cancerous and healthy cells, leading to unwanted toxicity and highlighting the urgent need for targeted therapies. In this study, we present a precision chemotype based on a quinoxalone-tethered adamantane framework developed via a metal- and light-free protocol. The compound selectively inhibits t(8;21) AML cell proliferation and induces cell death by disrupting growth and metabolic pathways, as demonstrated through bioassays, RNA sequencing, and proteomic analysis. Notably, it spares other leukemic and solid cancer cells, underscoring its specificity and potential as a targeted therapy for t(8;21) AML.