Abstract Acute Myeloid Leukemia (AML) is the most prevalent form of acute leukemia with an overall poor prognosis. Cancer cells including AML cells consume high glucose and show altered glucose metabolism, which increases glycosylation of intracellular proteins in a process called O-GlcNAcylation. We discovered that O-GlcNAcylation of several proteins is significantly increased in AML cells and inhibition of global O-GlcNAcylation leads to the death of AML cells. We also found that the transcription factor nuclear factor kappaB (NF-κB) c-Rel is mono-O-GlcNAcylated at serine residue 350 in AML cells. c-Rel controls the expression of several genes involved in AML cell survival and disease progression. We have developed a novel peptoid, a peptidomimetic agent called peptoid3, for specific targeting of O-GlcNAcylated c-Rel function. Our preliminary studies using AML cell lines show that the peptoid3 treatment significantly decreased the expression of multiple c-Rel-dependent genes involved in AML survival and caused death of AML cells. This is a unique and novel approach that specifically kills AML cells sparing normal white blood cells. This study will explore the ability of the novel agent, peptoid3, to control AML progression using primary AML cells from patients of various subtypes such as M1-M5 as well as using xenograft mouse models. Successful completion of this preclinical study will reveal O-GlcNAcylated c-Rel as a key player controlling AML cell growth and a potential therapeutic target. This study with future translational work has the potential to yield an oral therapeutic, which may significantly reduce the healthcare cost and improve the lives of patients suffering from AML.