4UX4

Crystal structure of human tankyrase 2 in complex with 1-methyl-7-(4- methylphenyl)-5-oxo-5,6-dihydro-1,6-naphthyridin-1-ium

Summary for 4UX4

• Entry DOI: 10.2210/pdb4ux4/pdb
• Descriptor: TANKYRASE-2, (1S)-1-methyl-7-(4-methylphenyl)-5-oxo-1,5-dihydro-1,6-naphthyridin-1-ium, ZINC ION, ... (6 entities in total)
• Functional Keywords: transferase, diphtheria toxin like fold, adp- ribosylation, transferase-transferase inhibitor complex
• Biological source: HOMO SAPIENS (HUMAN)
• Total number of polymer chains: 2
• Total formula weight: 55801.39

Authors

Haikarainen, T.,Lehtio, L. (deposition date: 2014-08-19, release date: 2015-06-10, Last modification date: 2024-05-08)

Primary citation

Kumpan, K.,Nathubhai, A.,Zhang, C.,Wood, P.J.,Lloyd, M.D.,Thompson, A.S.,Haikarainen, T.,Lehtio, L.,Threadgill, M.D.
Structure-Based Design, Synthesis and Evaluation in Vitro of Arylnaphthyridinones, Arylpyridopyrimidinones and Their Tetrahydro Derivatives as Inhibitors of the Tankyrases.
Bioorg.Med.Chem., 23:3013-, 2015

PubMed Abstract: The tankyrases are members of the PARP superfamily; they poly(ADP-ribosyl)ate their target proteins using NAD(+) as a source of electrophilic ADP-ribosyl units. The three principal protein substrates of the tankyrases (TRF1, NuMA and axin) are involved in replication of cancer cells; thus inhibitors of the tankyrases may have anticancer activity. Using structure-based drug design and by analogy with known 3-arylisoquinolin-1-one and 2-arylquinazolin-4-one inhibitors, series of arylnaphthyridinones, arylpyridinopyrimidinones and their tetrahydro-derivatives were synthesised and evaluated in vitro. 7-Aryl-1,6-naphthyridin-5-ones, 3-aryl-2,6-naphthyridin-1-ones and 3-aryl-2,7-naphthyridin-1-ones were prepared by acid-catalysed cyclisation of the corresponding arylethynylpyridinenitriles or reaction of bromopyridinecarboxylic acids with β-diketones, followed by treatment with NH3. The 7-aryl-1,6-naphthyridin-5-ones were methylated at 1-N and reduced to 7-aryl-1-methyl-1,2,3,4-tetrahydro-1,6-naphthyridin-5-ones. Cu-catalysed reaction of benzamidines with bromopyridinecarboxylic acids furnished 2-arylpyrido[2,3-d]pyrimidin-4-ones. Condensation of benzamidines with methyl 1-benzyl-4-oxopiperidine-3-carboxylate and deprotection gave 2-aryl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-ones, aza analogues of the known inhibitor XAV939. Introduction of the ring-N in the arylnaphthyridinones and the arylpyridopyrimidinones caused >1000-fold loss in activity, compared with their carbocyclic isoquinolinone and quinazolinone analogues. However, the 7-aryl-1-methyl-1,2,3,4-tetrahydro-1,6-naphthyridin-5-ones showed excellent inhibition of the tankyrases, with some examples having IC50=2nM. One compound (7-(4-bromophenyl)-1-methyl-1,2,3,4-tetrahydro-1,6-naphthyridin-5-one) showed 70-fold selectivity for inhibition of tankyrase-2 versus tankyrase-1. The mode of binding was explored through crystal structures of inhibitors in complex with tankyrase-2.

PubMed: 26026769
DOI: 10.1016/J.BMC.2015.05.005

Experimental method

X-RAY DIFFRACTION (1.8 Å)