4HYF

Structural basis and SAR for OD 270, a lead stage 1,2,4-triazole based specific Tankyrase1/2 inhibitor

Summary for 4HYF

• Entry DOI: 10.2210/pdb4hyf/pdb
• Related: 3KR7 3KR8 3P0N 3U9Y 4HKI 4HKN
• Descriptor: Tankyrase-2, NICOTINAMIDE, ZINC ION, ... (5 entities in total)
• Functional Keywords: catalytic fragment, parp, adp-ribosylation, ank repeat, chromosomal protein, glycosyltransferase, phosphorylation, telomere, transferase, translocation, transport, wnt-signalling, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• Biological source: Homo sapiens (human)
• Cellular location: Cytoplasm: Q9H2K2
• Total number of polymer chains: 3
• Total formula weight: 84051.77

Authors

Perdreau, H.,Ekblad, B.,Voronkov, A.,Holsworth, D.D.,Waaler, J.,Drewes, G.,Schueler, H.,Krauss, S.,Morth, J.P. (deposition date: 2012-11-13, release date: 2013-03-20, Last modification date: 2023-09-20)

Primary citation

Voronkov, A.,Holsworth, D.D.,Waaler, J.,Wilson, S.R.,Ekblad, B.,Perdreau-Dahl, H.,Dinh, H.,Drewes, G.,Hopf, C.,Morth, J.P.,Krauss, S.
Structural Basis and SAR for G007-LK, a Lead Stage 1,2,4-Triazole Based Specific Tankyrase 1/2 Inhibitor.
J.Med.Chem., 56:3012-3023, 2013

PubMed Abstract: Tankyrases 1 and 2 (TNKS1/2) are promising pharmacological biotargets with possible applications for the development of novel anticancer therapeutics. A focused structure-activity relationship study was conducted based on the tankyrase inhibitor JW74 (1). Chemical analoging of 1 improved the 1,2,4-triazole based core and led to 4-{5-[(E)-2-{4-(2-chlorophenyl)-5-[5-(methylsulfonyl)pyridin-2-yl]-4H-1,2,4-triazol-3-yl}ethenyl]-1,3,4-oxadiazol-2-yl}benzonitrile (G007-LK), a potent, "rule of 5" compliant and a metabolically stable TNKS1/2 inhibitor. G007-LK (66) displayed high selectivity toward tankyrases 1 and 2 with biochemical IC50 values of 46 nM and 25 nM, respectively, and a cellular IC50 value of 50 nM combined with an excellent pharmacokinetic profile in mice. The PARP domain of TNKS2 was cocrystallized with 66, and the X-ray structure was determined at 2.8 Å resolution in the space group P3221. The structure revealed that 66 binds to unique structural features in the extended adenosine binding pocket which forms the structural basis for the compound's high target selectivity and specificity. Our study provides a significantly optimized compound for targeting TNKS1/2 in vitro and in vivo.

PubMed: 23473363
DOI: 10.1021/jm4000566

Experimental method

X-RAY DIFFRACTION (2.8 Å)