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

  • J Med Chem. 2018 Feb 8;61(3):745-759. doi: 10.1021/acs.jmedchem.7b01254.
Roberto Pellicciari  1 ,  Paride Liscio  1 ,  Nicola Giacchè  1 ,  Francesca De Franco  1 ,  Andrea Carotti  2 ,  Janet Robertson  1 ,  Lucia Cialabrini  3 ,  Elena Katsyuba  4 ,  Nadia Raffaelli  3 ,  Johan Auwerx  4
Affiliations
  • 1. TES Pharma S.r.l. , IT-06073 Corciano, Perugia, Italy.
  • 2. Department of Pharmaceutical Sciences, University of Perugia , IT-06123 Perugia, Italy.
  • 3. Department of Agricultural, Food and Environmental Sciences, Polytechnic University of Marche , IT-60131 Ancona, Italy.
  • 4. Laboratory of Integrative and Systems Physiology, Interfaculty Institute of Bioengineering, École Polytechnique Fédérale de Lausanne CH-1015 Lausanne, Switzerland.
PMID: 29345930 DOI: 10.1021/acs.jmedchem.7b01254
Abstract

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.

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