8S4X の概要
| エントリーDOI | 10.2210/pdb8s4x/pdb |
| 分子名称 | Poly [ADP-ribose] polymerase tankyrase-2, 8-[bis(oxidanyl)amino]-2-(4-~{tert}-butylphenyl)-3~{H}-quinazolin-4-one, SULFATE ION, ... (6 entities in total) |
| 機能のキーワード | inhibitor, quinazolin-4-one, transferase, tankyrase 2 |
| 由来する生物種 | Homo sapiens (human) 詳細 |
| タンパク質・核酸の鎖数 | 4 |
| 化学式量合計 | 50857.97 |
| 構造登録者 | |
| 主引用文献 | Bosetti, C.,Kampasis, D.,Brinch, S.A.,Galera-Prat, A.,Karelou, M.,Dhakar, S.S.,Alaviuhkola, J.,Waaler, J.,Lehtio, L.,Kostakis, I.K. Substitutions at the C-8 position of quinazolin-4-ones improve the potency of nicotinamide site binding tankyrase inhibitors. Eur.J.Med.Chem., 288:117397-117397, 2025 Cited by PubMed Abstract: Human diphtheria toxin-like ADP-ribosyltransferases, PARPs and tankyrases, transfer ADP-ribosyl groups to other macromolecules, thereby controlling various signaling events in cells. They are considered promising drug targets, especially in oncology, and a vast number of inhibitors have already been successfully developed. These inhibitors typically occupy the nicotinamide binding site and extend along the NAD binding groove of the catalytic domain. Quinazolin-4-ones have been explored as compelling scaffolds for such inhibitors and we have identified a new position within the catalytic domain that has not been extensively studied yet. In this study, we investigate larger substituents at the C-8 position and, using X-ray crystallography, we demonstrate that nitro- and diol-substituents engage in new interactions with TNKS2, improving both affinity and selectivity. Both diol- and nitro-substituents exhibit intriguing inhibition of TNKS2, with the diol-based compound EXQ-1e displaying a pIC of 7.19, while the nitro-based compound EXQ-2d's pIC value is 7.86. Both analogues impact and attenuate the tankyrase-controlled WNT/β-catenin signaling with sub-micromolar IC. When tested against a wider panel of enzymes, the nitro-based compound EXQ-2d displayed high selectivity towards tankyrases, whereas the diol-based compound EXQ-1e also inhibited other PARPs. Compound EXQ-2d displays in vitro cell growth inhibition of the colon cancer cell line COLO 320DM, while compound EXQ-1e displays nonspecific cell toxicity. Collectively, the results offer new insights for inhibitor development targeting tankyrases and PARPs by focusing on the subsite between a mobile active site loop and the canonical nicotinamide binding site. PubMed: 39983556DOI: 10.1016/j.ejmech.2025.117397 主引用文献が同じPDBエントリー |
| 実験手法 | X-RAY DIFFRACTION (2.5 Å) |
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