Aminothiazolone Inhibitors Disrupt the Protein-RNA Interaction of METTL16 and Modulate the m⁶A RNA Modification

Area of Science:

• Chemical biology
• Molecular oncology
• RNA epigenetics

Background:

• Post-transcriptional modifications, particularly N6-methyladenosine (m6A), are critical regulatory mechanisms in eukaryotes.
• Methyltransferase-like protein 16 (METTL16) is a key regulator of m6A and implicated in cancer progression.
• Lack of specific small-molecule inhibitors hinders the study of METTL16's biological functions and therapeutic potential.

Purpose of the Study:

• To identify and characterize novel small-molecule inhibitors of METTL16.
• To develop chemical probes for investigating METTL16-mediated RNA regulation.
• To explore the therapeutic potential of targeting METTL16 in cancer.

Main Methods:

• High-throughput fluorescence-polarization (FP)-based screening for METTL16 inhibitors.
• Structure-activity relationship (SAR) studies for lead optimization.
• Biochemical assays to confirm inhibition of METTL16-RNA binding.

Main Results:

• Identification of a novel series of aminothiazolone-based METTL16 inhibitors.
• Discovery of compound 45 with potent single-digit micromolar inhibition of METTL16-RNA interaction.
• Validation of aminothiazolone derivatives as first-in-class METTL16 modulators.

Conclusions:

• Aminothiazolone derivatives represent a promising class of small-molecule inhibitors for METTL16.
• These inhibitors serve as valuable chemical probes for dissecting METTL16's role in biological systems.
• Targeting METTL16 with small molecules offers a potential therapeutic strategy for cancers.