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. Whilst the beneficial effects of NAD⁺ boosting are well established in mitochondrial fitness, metabolism, and lifespan, 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 increase NAD⁺ levels in cellular systems. Results of physicochemical properties, 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 in class molecule for evaluation of the therapeutic potential of ACMSD inhibition in treating disorders with perturbed NAD⁺ supply and/or homeostasis.
a-Amino-b-carboxymuconate-e-semialdehyde Decarboxylase (ACMSD) Inhibitors as Novel Modulators of de Novo Nicotinamide Adenine Dinucleotide (NAD+) Biosynthesis
Pellicciari, Roberto
;Liscio, Paride;Giacchè, Nicola;De Franco, Francesca;Carotti, Andrea;
2018
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. Whilst the beneficial effects of NAD⁺ boosting are well established in mitochondrial fitness, metabolism, and lifespan, 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 increase NAD⁺ levels in cellular systems. Results of physicochemical properties, 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 in class molecule for evaluation of the therapeutic potential of ACMSD inhibition in treating disorders with perturbed NAD⁺ supply and/or homeostasis.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
