High-Affinity Alkynyl Bisubstrate Inhibitors of Nicotinamide N-Methyltransferase (NNMT)

In this work, structure-based rational design led to the development of potent and selective alkynyl bisubstrate inhibitors of NNMT. The reported nicotinamide-SAM conjugate (named NS1) features an alkyne as a keydesign element that closely mimics the linear, 180° transition state geometry found in the NNMT-catalyzed SAM→ NAM (nicotinamide) methyl transfer reaction. NS1 was synthesized as a single enantiomer and diastereomer in 14 steps andfound to be a high-affinity, subnanomolar NNMT inhibitor. An X-ray co-crystal structure and structure-activityrelationship (SAR) study revealed the unique ability of an alkynyl linker to span the methyl transfer tunnel ofNNMT with ideal shape complementarity. The compounds reported in this work represent the most potent andselective NNMT inhibitors reported to date. The rational design principle described herein could potentially beextended to other methyltransferase enzymes.