Small Molecules Targeting Human N-Acetylmannosamine Kinase.

Area of Science:

• Biochemistry
• Glycobiology
• Medicinal Chemistry

Background:

• N-Acetylmannosamine kinase (MNK) is vital for synthesizing sialic acids, essential components of glycoconjugates.
• Sialylated glycoconjugates influence critical biological processes, including immune responses and cancer development.

Purpose of the Study:

• To discover and validate novel, specific inhibitors of MNK.
• To explore the therapeutic potential of targeting MNK for diseases associated with aberrant sialic acid metabolism.

Main Methods:

• High-throughput screening of a diverse library of drug-like small molecules.
• Utilized orthogonal assays for robust validation of identified hits.
• Employed molecular modeling to elucidate inhibitor binding modes within the MNK active site.

Main Results:

• Identified four distinct small molecules exhibiting inhibitory activity against MNK.
• Achieved IC50 values in the low-micromolar range, indicating potent inhibition.
• Molecular modeling suggested binding to either the sugar or ATP-binding pocket, or both, of MNK.

Conclusions:

• The identified compounds are promising MNK inhibitors.
• These inhibitors offer a potential strategy for downregulating sialic acid content in glycoconjugates.
• The compounds can be valuable tools for investigating the role of sialic acids in disease pathogenesis.