Search

Searchingfor selective tankyrases (TNKSs) inhibitors, a new smallseries of 6,8-disubstituted triazolo[4,3-b]piridazineshas been synthesized and characterized biologically. Structure-basedoptimization of the starting hit compound NNL (3) promptedus to the discovery of 4-(2-(6-methyl-[1,2,4]triazolo[4,3-b]pyridazin-8-ylamino)ethyl)phenol (12), alow nanomolar selective TNKSs inhibitor working as NAD isostere asascertained by crystallographic analysis. Preliminary biological datacandidate this new class of derivatives as a powerful pharmacologicaltools in the unraveling of TNKS implications in physiopathologicalconditions. [ABSTRACT FROM AUTHOR]

The nuclear receptor ss DAF-12 has been recognized as the key molecular player regulating the life cycle of the nematode parasite Strongyloides stercoralis . ss DAF-12 ligands permit the receptor to function as an on/off switch modulating infection, making it vulnerable to therapeutic intervention. In this study, we report the design and synthesis of a set of novel dafachronic acid derivatives, which were used to outline the first structure-activity relationship targeting the ss DAF-12 receptor and to unveil hidden properties shared by the molecular shape of steroidal ligands that are relevant to the receptor binding and modulation. Moreover, biological results led to the discovery of sulfonamide 3 as a submicromolar ss DAF-12 agonist endowed with a high receptor selectivity, no toxicity, and improved properties, as well as to the identification of unprecedented ss DAF-12 antagonists that can be exploited in the search for novel chemical tools and alternative therapeutic approaches for treating parasitism such as Strongyloidiasis.

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 50 = 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.