Exploration of the nicotinamide-binding site of the tankyrases, identifying 3-arylisoquinolin-1-ones as potent and selective inhibitors in vitro. Issue 17 (1st September 2015)

• Record Type: Journal Article
• Authors: Paine, Helen A.; Nathubhai, Amit; Woon, Esther C.Y.; Sunderland, Peter T.; Wood, Pauline J.; Mahon, Mary F.; Lloyd, Matthew D.; Thompson, Andrew S.; Haikarainen, Teemu; Narwal, Mohit; Lehtiö, Lari; Threadgill, Michael D.
• Is Part Of: Bioorganic & medicinal chemistry. Volume 23:Issue 17(2015)
• Page Start: 5891
• Page End: 5908
• Publication Date: 2015-09-01
• Subjects: Tankyrase -- TNKS -- Naphthyridinone -- 7-Aryl-1-methyl-1, 2, 3, 4-tetrahydro-1, 6-naphthyridin-5-one -- Crystal structure; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; Biochemistry -- Periodicals; Chemistry, Clinical -- Periodicals; Chemistry, Organic -- Periodicals; Chimie bio-organique -- Périodiques; Chimie pharmaceutique -- Périodiques; 615.19
• DOI: 10.1016/j.bmc.2015.06.061
• Languages: English
• ISSNs: 0968-0896

Abstract

Graphical abstract: Abstract: 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.