SGC 0946

SGC 0946 is a potent and selective small molecule inhibitor of the histone methyltransferase DOT1L (disruptor of telomeric silencing 1-like). Developed as a chemical probe by the Structural Genomics Consortium (SGC), it specifically targets the methyltransferase activity of DOT1L, which is responsible for the mono-, di-, and tri-methylation of histone H3 on lysine 79 (H3K79). DOT1L dysregulation is frequently implicated in leukemias, particularly those involving MLL (KMT2A) gene rearrangements, and recent research suggests its potential utility in other hematological malignancies like marginal zone lymphoma (MZL). SGC 0946 demonstrates high potency in cellular assays, effectively reducing H3K79 methylation and inhibiting the proliferation of sensitive cancer cell lines, including those with acquired resistance to targeted therapies like BTK and PI3K inhibitors.