4hyf | pdb_00004hyf
Structural basis and SAR for OD 270, a lead stage 1,2,4-triazole based specific Tankyrase1/2 inhibitor
Structural highlights
FunctionTNKS2_HUMAN Poly-ADP-ribosyltransferase involved in various processes such as Wnt signaling pathway, telomere length and vesicle trafficking. Acts as an activator of the Wnt signaling pathway by mediating poly-ADP-ribosylation of AXIN1 and AXIN2, 2 key components of the beta-catenin destruction complex: poly-ADP-ribosylated target proteins are recognized by RNF146, which mediates their ubiquitination and subsequent degradation. Also mediates poly-ADP-ribosylation of BLZF1 and CASC3, followed by recruitment of RNF146 and subsequent ubiquitination. Mediates poly-ADP-ribosylation of TERF1, thereby contributing to the regulation of telomere length. May also regulate vesicle trafficking and modulate the subcellular distribution of SLC2A4/GLUT4-vesicles.[1] [2] [3] [4] Publication Abstract from PubMedTankyrases 1 and 2 (TNKS1/2) are promising pharmacological biotargets with possible applications for the development of novel anti-cancer 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-triaz ol-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 co-crystallized with 66 and the X-ray structure was determined at a 2.8 A 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 compounds high target selectivity and specificity. Our study provides a significantly optimized compound for targeting TNKS1/2 in vitro and in vivo. Structural basis and SAR for G007-LK, a lead stage 1,2,4-triazole based specific tankyrase 1/2 inhibitor.,Voronkov A, Holsworth DD, Waaler J, Wilson SR, Ekblad B, Perdreau-Dahl H, Dinh H, Drewes G, Hopf C, Morth JP, Krauss S J Med Chem. 2013 Mar 11. PMID:23473363[5] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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