EPZ004777 is a selective inhibitor of the histone methyltransferase DOT1L, an enzyme involved in epigenetic regulation through methylation of histone H3 at lysine 79 (H3K79). Its primary application lies in cancer research, particularly in the study of mixed lineage leukemia (MLL) rearranged leukemias. These aggressive forms of leukemia are driven by abnormal gene expression patterns caused by MLL gene translocations, which depend on DOT1L activity for oncogenic transformation. By inhibiting DOT1L, EPZ004777 reduces H3K79 methylation at MLL fusion target genes, leading to downregulation of leukemogenic genes such as HOXA9 and MEIS1. This results in suppression of leukemia cell proliferation and induction of apoptosis in MLL-rearranged cell lines. Due to this mechanism, EPZ004777 serves as a valuable tool compound for validating DOT1L as a therapeutic target and for exploring epigenetic therapies in hematological malignancies. It has also been used in preclinical studies to investigate the role of DOT1L in other cancers and cellular processes, including cardiac development and inflammation. While not used clinically, EPZ004777 paved the way for the development of more potent and bioavailable DOT1L inhibitors for potential therapeutic use.