Fragment screening ofN-acetylmannosamine kinase reveals noncarbohydrate inhibitors

Abstract

Many biological processes from infection to tumor immune evasion are controlled by cell surface sialylation. To gather further insight into these processes, methods to alter cell surface sialylation are required. One way to achieve this is inhibiting the key enzyme of sialic acid de novo biosynthesis, the intracellular bifunctional UDP-N-acetylglucosamine epimerase/N-acetylmannosamine kinase (GNE/MNK). Here, we present low molecular weight inhibitors of MNK activity based on picolinic acid derivatives. They were identified in a fragment screening using19F NMR and validated in a biochemical inhibition assay followed by a structure–activity relationship analysis and docking. The optimized compound 6-carbamoylpicolinic acid inhibits MNK with a double-digit micromolar affinity. Its low molecular weight (166 Da) renders this picolinic acid derivative an exquisite starting point for the development of high-affinity MNK inhibitors, which may serve as molecular probes or lead candidates in future.