An update on DOT1L^WT/MUT modulators as a promising anticancer strategy

Disruptor of telomeric silencing 1-like (DOT1L) is the only identified H3K79 methyltransferase and its dysregulation, mutations, or aberrant activity are closely implicated in the pathogenesis and progression of various diseases. Due to their key roles in leukemogenesis and lung carcinogenesis, DOT1L and its mutations have been studied as attractive therapeutic targets for over a decade, resulting in the identification of numerous DOT1L inhibitors. Herein, we provide an overview of the structural features of DOT1L^WT/MUT, as well as their associated signaling pathways and diseases. We summarize recent advances in orthosteric and allosteric DOT1L inhibitors, with their design strategies comprehensively analyzed based on the "Induced-fit" allosteric model. Furthermore, emerging strategies including protein-protein interaction (PPI) inhibitors, proteolysis-targeting chimeras (PROTACs) and combination therapies are also introduced. Finally, we discuss current challenges and future opportunities to provide valuable references for the development of next-generation DOT1L-targeted therapeutics.