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

Area of Science:

• Biochemistry and Molecular Biology
• Cancer Research
• Drug Discovery

Background:

• Disruptor of telomeric silencing 1-like (DOT1L) is the sole H3K79 methyltransferase, crucial in various disease pathologies.
• DOT1L dysregulation is implicated in leukemogenesis and lung carcinogenesis, making it a significant therapeutic target.

Purpose of the Study:

• To provide a comprehensive overview of DOT1L structure, signaling pathways, and associated diseases.
• To summarize recent advancements in DOT1L inhibitor development, including orthosteric and allosteric strategies.
• To introduce emerging therapeutic modalities targeting DOT1L, such as PPI inhibitors and PROTACs.

Main Methods:

• Structural analysis of wild-type (WT) and mutant DOT1L.
• Review of signaling pathways and disease associations.
• Analysis of inhibitor design strategies based on the "Induced-fit" allosteric model.

Main Results:

• Detailed examination of DOT1L structural features and their implications in disease.
• Summary of current orthosteric and allosteric DOT1L inhibitors.
• Introduction to novel therapeutic approaches like PPI inhibitors and PROTACs.

Conclusions:

• DOT1L remains a promising target for cancer therapy.
• Advances in inhibitor design and emerging strategies offer new avenues for drug development.
• Further research is needed to overcome challenges and develop next-generation DOT1L-targeted therapeutics.