3 years ago

α-Amino-β-carboxymuconate-ε-semialdehyde Decarboxylase (ACMSD) Inhibitors as Novel Modulators of De Novo Nicotinamide Adenine Dinucleotide (NAD+) Biosynthesis

α-Amino-β-carboxymuconate-ε-semialdehyde
Decarboxylase (ACMSD) Inhibitors as Novel Modulators of De Novo Nicotinamide
Adenine Dinucleotide (NAD+) Biosynthesis
Janet Robertson, Lucia Cialabrini, Francesca De Franco, Nicola Giacchè, Johan Auwerx, Andrea Carotti, Elena Katsyuba, Paride Liscio, Nadia Raffaelli, Roberto Pellicciari
NAD+ has a central function in linking cellular metabolism to major cell-signaling and gene-regulation pathways. Defects in NAD+ homeostasis underpin a wide range of diseases, including cancer, metabolic disorders, and aging. Although the beneficial effects of boosting NAD+ on mitochondrial fitness, metabolism, and lifespan are well established, to date, no therapeutic enhancers of de novo NAD+ biosynthesis have been reported. Herein we report the discovery of 3-[[[5-cyano-1,6-dihydro-6-oxo-4-(2-thienyl)-2-pyrimidinyl]thio]methyl]phenylacetic acid (TES-1025, 22), the first potent and selective inhibitor of human ACMSD (IC50 = 0.013 μM) that increases NAD+ levels in cellular systems. The results of physicochemical-property, ADME, and safety profiling, coupled with in vivo target-engagement studies, support the hypothesis that ACMSD inhibition increases de novo NAD+ biosynthesis and position 22 as a first-class molecule for the evaluation of the therapeutic potential of ACMSD inhibition in treating disorders with perturbed NAD+ supply or homeostasis.

Publisher URL: http://dx.doi.org/10.1021/acs.jmedchem.7b01254

DOI: 10.1021/acs.jmedchem.7b01254

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