Open AccessHigh-Affinity Alkynyl Bisubstrate Inhibitors of Nicotinamide N-Methyltransferase (NNMT)
Author(s) -
Rocco L. Policarpo,
Ludovic Decultot,
Elizabeth May,
Petr Kuzmič,
Samuel Carlson,
Danny Huang,
Victor C. Chu,
Brandon A. Wright,
Saravanakumar Dhakshinamoorthy,
Aimo Kannt,
Shilpa Rani,
Sreekanth Dittakavi,
Joseph D. Panarese,
Rachelle Gaudet,
Matthew D. Shair
Publication year - 2019
Publication title -
journal of medicinal chemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.01
H-Index - 261
eISSN - 1520-4804
pISSN - 0022-2623
DOI - 10.1021/acs.jmedchem.9b01238
Subject(s) - chemistry , nicotinamide , enzyme , stereochemistry , cofactor , rational design , methyltransferase , biochemistry , structure–activity relationship , methylation , in vitro , dna , genetics , biology
Nicotinamide N -methyltransferase (NNMT) is a metabolic enzyme that methylates nicotinamide (NAM) using cofactor S -adenosylmethionine (SAM). NNMT overexpression has been linked to diabetes, obesity, and various cancers. 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 key design element that closely mimics the linear, 180° transition state geometry found in the NNMT-catalyzed SAM → NAM methyl transfer reaction. NS1 was synthesized in 14 steps and found to be a high-affinity, subnanomolar NNMT inhibitor. An X-ray cocrystal structure and SAR study revealed the ability of an alkynyl linker to span the methyl transfer tunnel of NNMT with ideal shape complementarity. The compounds reported in this work represent the most potent and selective NNMT inhibitors reported to date. The rational design principle described herein could potentially be extended to other methyltransferase enzymes.