Summary for 6TKQ
| Entry DOI | 10.2210/pdb6tkq/pdb |
| Descriptor | Tankyrase-2, ZINC ION, ~{N}-[3-[5-(5-ethoxypyridin-2-yl)-4-phenyl-1,2,4-triazol-3-yl]cyclobutyl]-1,5-naphthyridine-4-carboxamide, ... (4 entities in total) |
| Functional Keywords | inhibitor, complex, poly-adp-ribosylation, enzyme, transferase |
| Biological source | Homo sapiens (Human) |
| Total number of polymer chains | 2 |
| Total formula weight | 55713.43 |
| Authors | Sowa, S.T.,Lehtio, L. (deposition date: 2019-11-28, release date: 2020-07-08, Last modification date: 2024-01-24) |
| Primary citation | Waaler, J.,Leenders, R.G.G.,Sowa, S.T.,Alam Brinch, S.,Lycke, M.,Nieczypor, P.,Aertssen, S.,Murthy, S.,Galera-Prat, A.,Damen, E.,Wegert, A.,Nazare, M.,Lehtio, L.,Krauss, S. Preclinical Lead Optimization of a 1,2,4-Triazole Based Tankyrase Inhibitor. J.Med.Chem., 63:6834-6846, 2020 Cited by PubMed Abstract: Tankyrases 1 and 2 are central biotargets in the WNT/β-catenin signaling and Hippo signaling pathways. We have previously developed tankyrase inhibitors bearing a 1,2,4-triazole moiety and binding predominantly to the adenosine binding site of the tankyrase catalytic domain. Here we describe a systematic structure-guided lead optimization approach of these tankyrase inhibitors. The central 1,2,4-triazole template and cyclobutyl linker of the lead compound were left unchanged, while side-group East, West, and South moieties were altered by introducing different building blocks defined as point mutations. The systematic study provided a novel series of compounds reaching picomolar IC inhibition in WNT/βcatenin signaling cellular reporter assay. The novel optimized lead resolves previous atropisomerism, solubility, and Caco-2 efflux liabilities. shows a favorable ADME profile, including improved Caco-2 permeability and oral bioavailability in mice, and exhibits antiproliferative efficacy in the colon cancer cell line COLO 320DM PubMed: 32511917DOI: 10.1021/acs.jmedchem.0c00208 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.5 Å) |
Structure validation
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