Recent advances in small molecules targeting the METTL3.

Area of Science:

• Biochemistry
• Molecular Biology
• Oncology

Background:

• * N⁶-methyladenosine (m⁶A) is the most abundant internal mRNA modification in eukaryotes, regulating gene expression.
• * Methyltransferase-like 3 (METTL3) is the core enzyme responsible for m⁶A deposition.
• * METTL3 influences tumorigenesis via m⁶A-dependent and independent pathways, making it a promising cancer therapeutic target.

Purpose of the Study:

• * To review recent progress in discovering small molecules targeting METTL3.
• * To discuss strategies, structural features, and challenges in developing METTL3 inhibitors.
• * To provide insights for designing novel METTL3-targeted cancer therapeutics.

Main Methods:

• * Literature review of recent studies on METTL3 inhibitors.
• * Analysis of small molecule inhibitors including substrate-competitive and allosteric inhibitors.
• * Examination of proteolysis-targeting chimeras (PROTACs) for METTL3 degradation.

Main Results:

• * Several classes of small molecules targeting METTL3 have been identified.
• * Diverse strategies are employed for discovering these inhibitors.
• * Structural features of inhibitors and their mechanisms of action are discussed.

Conclusions:

• * METTL3 is a validated target for cancer therapy.
• * Small molecules and PROTACs show potential for METTL3 inhibition.
• * Further research is needed to overcome challenges and advance METTL3-targeted therapies.