molecules of the month

Context. “Compound 14” (Shionogi Pharmaceuticals) is a nicotinamide N-methyltransferase (NNMT) inhibitor. For some “difficult to drug” targets such as protein-protein interactions, peptides are attractive therapeutic modalities due to their high binding specificity and synthetic accessibility. Macrocyclization of peptides may help improve upon their typical drawbacks, such as poor stability and cell permeability; however, the therapeutic efficacy of macrocyclic peptides is also limited by their molecular sizes and polar surface areas. To address these issues, Shionogi scientists adopted a novel ″Peptide-to-Small Molecule″ strategy that was based on structural hopping of macrocyclic peptides into nonpeptide small molecules. To evaluate the strategy, NNMT, a widely expressed epigenetic enzyme that has been associated with several diseases, was used. Starting from a macrocyclic peptide hit…