4LI6
TANKYRASE-1 Complexed with small molecule inhibitor N-[(4-oxo-3,4-dihydroquinazolin-2-yl)methyl]-3-phenyl-N-(thiophen-2-ylmethyl)propanamide
Summary for 4LI6
| Entry DOI | 10.2210/pdb4li6/pdb |
| Related | 4LI7 4LI8 |
| Descriptor | Tankyrase-1, ZINC ION, SULFATE ION, ... (5 entities in total) |
| Functional Keywords | transferase-transferase inhibitor complex, transferase/transferase inhibitor |
| Biological source | Homo sapiens (human) |
| Cellular location | Cytoplasm: O95271 |
| Total number of polymer chains | 2 |
| Total formula weight | 52237.55 |
| Authors | Kirby, C.A.,Stams, T. (deposition date: 2013-07-02, release date: 2013-08-14, Last modification date: 2024-02-28) |
| Primary citation | Shultz, M.D.,Cheung, A.K.,Kirby, C.A.,Firestone, B.,Fan, J.,Chen, C.H.,Chen, Z.,Chin, D.N.,Dipietro, L.,Fazal, A.,Feng, Y.,Fortin, P.D.,Gould, T.,Lagu, B.,Lei, H.,Lenoir, F.,Majumdar, D.,Ochala, E.,Palermo, M.G.,Pham, L.,Pu, M.,Smith, T.,Stams, T.,Tomlinson, R.C.,Toure, B.B.,Visser, M.,Wang, R.M.,Waters, N.J.,Shao, W. Identification of NVP-TNKS656: The Use of Structure-Efficiency Relationships To Generate a Highly Potent, Selective, and Orally Active Tankyrase Inhibitor. J.Med.Chem., 56:6495-6511, 2013 Cited by PubMed Abstract: Tankyrase 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. PubMed: 23844574DOI: 10.1021/jm400807n PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.05 Å) |
Structure validation
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