Nicotinamide adenine dinucleotide (NAD + ) is a cosubstrate for several enzymes, including the sirtuin family of NAD + -dependent protein deacylases. Beneficial effects of increased NAD + levels and sirtuin activation on mitochondrial homeostasis, organismal metabolism and lifespan have been established across species. Here we show that α-amino-β-carboxymuconate-ε-semialdehyde decarboxylase (ACMSD), the enzyme that limits the proportion of ACMS able to undergo spontaneous cyclisation in the de novo NAD + synthesis pathway, controls cellular NAD + levels via an evolutionary conserved mechanism from C. elegans to the mouse. Genetic and pharmacological inhibition of ACMSD boosts de novo NAD + synthesis and SIRT1 activity, ultimately enhancing mitochondrial function. We furthermore characterized a series of potent and selective ACMSD inhibitors, which, given the restricted ACMSD expression in kidney and liver, are of high therapeutic interest to protect these tissues from injury. ACMSD hence is a key modulator of cellular NAD + levels, sirtuin activity, and mitochondrial homeostasis in kidney and liver.

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 (IC = 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.

No abstract

No abstract

Searching for selective tankyrases (TNKSs) inhibitors, a new small series of 6,8-disubstituted triazolo[4,3-b]piridazines has been synthesized and characterized biologically. Structure-based optimization of the starting hit compound NNL (3) prompted us to the discovery of 4-(2-(6-methyl-[1,2,4]triazolo[4,3-b]pyridazin-8-ylamino)ethyl)-phenol (12), a low nanomolar selective TNKSs inhibitor working as NAD isostere as ascertained by crystallographic analysis. Preliminary biological data candidate this new class of derivatives as a powerful pharmacological tools in the unraveling of TNKS implications in physiopathological conditions.