NNMT is a metabolic enzyme responsible for the methylation of nicotinamide (NCA) using the cofactor S-adenosylmethionine (SAM), resulting in the production of 1-methylnicotinamide (1MNA) and S-adenosylhomocysteine (SAH). Abnormal NNMT expression is implicated in several human diseases, including diabetes, obesity, and a variety of cancers. The successful development of potent and selective NNMT inhibitors would aid efforts to further elucidate NNMT’s role in various disease pathologies, potentially enabling new therapeutic strategies to treat a subset of cancers and metabolic diseases. Toward this end, we utilized structure-based computationally-guided rational design to develop potent bisubstrate inhibitors of NNMT. Specifically, we noted that in the NNMT cocrystal structure the NCA and SAH nitrogen and sulfur atoms, respectively, are positioned ca. 4 Å apart and reside in a “tunnel” that facilitates the SN2-type methyl transfer reaction. We envisioned an alkyne as the optimal linker between an NCA-like and a SAH-like fragment. The resultant alkynyl bisubstrate inhibitor, NS1, was synthesized asymmetrically in thirteen steps and found to be a 6 nM NNMT inhibitor, the most potent reported to date. Structure-activity relationship (SAR) studies revealed the alkynyl stereocenter and the nicotinamide amide functionality to be key contributors to NS1’s potency. NS1 is currently being evaluated for selectivity against related methyltransferases and is also being tested in a growth-inhibition panel against 489 cancer cell lines.

Alkynyl bisubstrate inhibitors of nicotinamide N-methyltransferase (NNMT)

256th National Meeting (2018)

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