4li6 | pdb_00004li6
TANKYRASE-1 Complexed with small molecule inhibitor N-[(4-oxo-3,4-dihydroquinazolin-2-yl)methyl]-3-phenyl-N-(thiophen-2-ylmethyl)propanamide
Structural highlights
Function[TNKS1_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 (PARsylation) 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 PARsylation of BLZF1 and CASC3, followed by recruitment of RNF146 and subsequent ubiquitination. Mediates PARsylation of TERF1, thereby contributing to the regulation of telomere length. Involved in centrosome maturation during prometaphase by mediating PARsylation of HEPACAM2/MIKI. May also regulate vesicle trafficking and modulate the subcellular distribution of SLC2A4/GLUT4-vesicles. May be involved in spindle pole assembly through PARsylation of NUMA1.[1] [2] [3] [4] [5] [6] Publication Abstract from PubMedTankyrase 1 and 2 have been shown to be redundant, druggable nodes in the Wnt pathway. As such, there has been intense interest in developing agents suitable for modulating the Wnt pathway in vivo by targeting this enzyme pair. By utilizing a combination of structure based design and LipE based structure efficiency relationships, the core of XAV939 was optimized into a more stable, more efficient but less potent dihydropyran motif 7. This core was combined with elements of screening hits 2, 19 and 33 and resulted in highly potent, selective tankyrase inhibitors that are novel three pocket binders. NVP-TNKS656 (43) was identified as an orally active antagonist of Wnt pathway activity in the MMTV-Wnt1 mouse xenograft model. With an enthalpy-driven thermodynamic signature of binding, highly favorable physicochemical properties and high lipophilic efficiency, NVP-TNKS656 is a novel tankyrase inhibitor that is well suited for further in vivo validation studies. Identification of NVP-TNKS656 - The Use of Structure Efficiency Relationships to Generate a Highly Potent, Selective and Orally Active Tankyrase Inhibitor.,Shultz MD, Cheung AK, Kirby CA, Firestone B, Fan J, Chen Z, Chin DN, Dipietro L, Fazal A, Feng Y, Fortin PD, Gould T, Lagu B, Lei H, Lenoir F, Majumdar D, Ochala E, Palermo MG, Pham L, Pu M, Smith T, Stams T, Tomlinson R, Toure BB, Visser M, Wang R, Waters NJ, Shao W J Med Chem. 2013 Jul 11. PMID:23844574[7] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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