Recent Advances and Perspectives of Small Molecule Modulators Targeting DOT1L

Disruptor of telomeric silencing 1-like (DOT1L), as the sole histone methyltransferase (HMT) for lysine 79 on histone H3 (H3K79), has become a promising therapeutic target for various diseases. DOT1L plays a critical role in the self-renewal of hematopoietic stem cells, B cell differentiation, and neural development. In acute leukemia (AML) carrying MLL rearrangements (MLL-r), this enzyme is aberrantly recruited to oncogene promoters, leading to excessive methylation of H3K79 and persistent activation of pro-proliferative transcription programs such as HOXA9 . In addition, abnormal expression, mutations, protein interactions, and nonenzymatic functions of DOT1L play important roles in various diseases. Modulators targeting DOT1L have been developed for more than a decade, and compounds such as competitive inhibitors, protein–protein interaction (PPI) inhibitors, and degraders block DOT1L’s pathogenic functions through various pharmacological mechanisms. Challenges and opportunities are discussed in this perspective, aiming to provide valuable insights for the future design of DOT1L modulators.