Structure–Efficiency Relationship of [1,2,4]Triazol-3-ylamines as Novel Nicotinamide Isosteres that Inhibit Tankyrases

Shultz, Michael D.; Majumdar, Dyuti; Chin, Donovan N.; Fortin, Pascal D.; Feng, Yun; Gould, Ty; Kirby, C.A.; Stams, Travis; Waters, Nigel J.; Shao, Wenlin

doi:10.1021/jm400826j

Cited by 27 publications

(32 citation statements)

References 35 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…46 Compound 7 uses an amino-1,2,4-triazole to make the requisite H-bonds within the nicotinamide-binding site, 47 whereas 8 uses a dihydropyranopyrimidine to bind there. 48 IWR1 9 49 and G007-LK 10 35,50 bind to the adenine-binding site alone.…”

Section: Introductionmentioning

confidence: 99%

Exploration of the nicotinamide-binding site of the tankyrases, identifying 3-arylisoquinolin-1-ones as potent and selective inhibitors in vitro

Paine

Nathubhai

Woon

et al. 2015

Bioorganic & Medicinal Chemistry

View full text Add to dashboard Cite

Tankyrases-1 and -2 (TNKS-1 and TNKS-2) have three cellular roles which make them important targets in cancer. Using NAD(+) as a substrate, they poly(ADP-ribosyl)ate TRF1 (regulating lengths of telomeres), NuMA (facilitating mitosis) and axin (in wnt/β-catenin signalling). Using molecular modelling and the structure of the weak inhibitor 5-aminoiso quinolin-1-one, 3-aryl-5-substituted-isoquinolin-1-ones were designed as inhibitors to explore the structure-activity relationships (SARs) for binding and to define the shape of a hydrophobic cavity in the active site. 5-Amino-3-arylisoquinolinones were synthesised by Suzuki-Miyaura coupling of arylboronic acids to 3-bromo-1-methoxy-5-nitro-isoquinoline, reduction and O-demethylation. 3-Aryl-5-methylisoquinolin-1-ones, 3-aryl-5-fluoroisoquinolin-1-ones and 3-aryl-5-methoxyisoquinolin-1-ones were accessed by deprotonation of 3-substituted-N,N,2-trimethylbenzamides and quench with an appropriate benzonitrile. SAR around the isoquinolinone core showed that aryl was required at the 3-position, optimally with a para-substituent. Small meta-substituents were tolerated but groups in the ortho-positions reduced or abolished activity. This was not due to lack of coplanarity of the rings, as shown by the potency of 4,5-dimethyl-3-phenylisoquinolin-1-one. Methyl and methoxy were optimal at the 5-position. SAR was rationalised by modelling and by crystal structures of examples with TNKS-2. The 3-aryl unit was located in a large hydrophobic cavity and the para-substituents projected into a tunnel leading to the exterior. Potency against TNKS-1 paralleled potency against TNKS-2. Most inhibitors were highly selective for TNKSs over PARP-1 and PARP-2. A range of highly potent and selective inhibitors is now available for cellular studies.

show abstract

Section: Introductionmentioning

confidence: 99%

Exploration of the nicotinamide-binding site of the tankyrases, identifying 3-arylisoquinolin-1-ones as potent and selective inhibitors in vitro

Paine

Nathubhai

Woon

et al. 2015

Bioorganic & Medicinal Chemistry

View full text Add to dashboard Cite

show abstract

“…Protein crystallography has also helped to rationalize the observed selectivity of some of the inhibitors [14][15][16] and it has been utilized in the development of several TNKS inhibitor scaffolds. 10,17 The donor NAD + binding groove of the ARTD domain has two sub-sites, namely the nicotinamide (NI) and the adenosine (ADE) sites, which have been targeted by inhibitors. 7 The known TNKS inhibitors such as 1-4 ( Fig.…”

Section: Introductionmentioning

confidence: 99%

Discovery of potent and selective nonplanar tankyrase inhibiting nicotinamide mimics

Nkizinkiko

Kumar

Jeankumar

et al. 2015

Bioorganic & Medicinal Chemistry

View full text Add to dashboard Cite

“…Furthermore, it was also assessed as Wnt pathway diruptor. In parallel to this work, Shultz et al 23 discovered that [1,2,4]-triazol-3-ylamine derivatives are also able to inhibit TNKSs by binding in a similar manner as our molecule. These new classes of compounds are promising isosteres of nicotinamide derivatives and can be considered new powerful pharmacological tools in the unravelling of TNKS implications in physiopathological conditions.…”

Section: Resultsmentioning

confidence: 54%

Design, Synthesis, Crystallographic Studies, and Preliminary Biological Appraisal of New Substituted Triazolo[4,3-b]pyridazin-8-amine Derivatives as Tankyrase Inhibitors

et al. 2014

View full text Add to dashboard Cite

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.

show abstract

Structure–Efficiency Relationship of [1,2,4]Triazol-3-ylamines as Novel Nicotinamide Isosteres that Inhibit Tankyrases

Cited by 27 publications

References 35 publications

Exploration of the nicotinamide-binding site of the tankyrases, identifying 3-arylisoquinolin-1-ones as potent and selective inhibitors in vitro

Exploration of the nicotinamide-binding site of the tankyrases, identifying 3-arylisoquinolin-1-ones as potent and selective inhibitors in vitro

Discovery of potent and selective nonplanar tankyrase inhibiting nicotinamide mimics

Design, Synthesis, Crystallographic Studies, and Preliminary Biological Appraisal of New Substituted Triazolo[4,3-b]pyridazin-8-amine Derivatives as Tankyrase Inhibitors

Contact Info

Product

Resources

About