4UVX

Crystal structure of human tankyrase 2 in complex with 3-(4- chlorophenyl)-5-fluoro-1,2-dihydroisoquinolin-1-one

Summary for 4UVX

• Entry DOI: 10.2210/pdb4uvx/pdb
• Related: 4UVL 4UVN 4UVO 4UVP 4UVS 4UVT 4UVU 4UVV 4UVW 4UVY 4UVZ
• Descriptor: TANKYRASE-2, SULFATE ION, GLYCEROL, ... (6 entities in total)
• Functional Keywords: transferase, protein-ligand complex, diphtheria toxin like fold, adp- ribosylation, transferase-transferase inhibitor complex
• Biological source: HOMO SAPIENS (HUMAN)
• Total number of polymer chains: 2
• Total formula weight: 55846.16

Authors

Haikarainen, T.,Narwal, M.,Lehtio, L. (deposition date: 2014-08-08, release date: 2015-07-29, Last modification date: 2024-05-08)

Primary citation

Paine, H.A.,Nathubhai, A.,Woon, E.C.Y.,Sunderland, P.T.,Wood, P.J.,Mahon, M.F.,Lloyd, M.D.,Thompson, A.S.,Haikarainen, T.,Narwal, M.,Lehtio, L.,Threadgill, M.D.
Exploration of the Nicotinamide-Binding Site of the Tankyrases, Identifying 3-Arylisoquinolin-1-Ones as Potent and Selective Inhibitors in Vitro.
Bioorg.Med.Chem., 23:5891-, 2015

PubMed 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.

PubMed: 26189030
DOI: 10.1016/J.BMC.2015.06.061

Experimental method

X-RAY DIFFRACTION (1.95 Å)