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.
MeSH terms
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Adenosine Diphosphate Ribose / metabolism
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Chromatography, High Pressure Liquid
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Crystallography, X-Ray
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Drug Design
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Enzyme Inhibitors / chemical synthesis*
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Enzyme Inhibitors / pharmacology*
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Humans
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Indicators and Reagents
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Luciferases / genetics
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Mass Spectrometry
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Models, Molecular
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Molecular Conformation
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Pyridazines / chemical synthesis*
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Pyridazines / pharmacology*
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Recombinant Proteins / drug effects
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Structure-Activity Relationship
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Tankyrases / antagonists & inhibitors*
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Triazoles / chemical synthesis*
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Triazoles / pharmacology*
Substances
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4-(2-(6-methyl-(1,2,4)triazolo(4,3-b)pyridazin-8-ylamino)ethyl)phenol
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Enzyme Inhibitors
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Indicators and Reagents
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Pyridazines
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Recombinant Proteins
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Triazoles
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Adenosine Diphosphate Ribose
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Luciferases
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Tankyrases
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TNKS protein, human