@article{uoadl:3488611,
    volume = "288",
    journal = "European Journal of Medicinal Chemistry Reports",
    keywords = "Antineoplastic Agents; Binding Sites; Cell Line, Tumor; Cell Proliferation; Crystallography, X-Ray; Dose-Response Relationship, Drug; Drug Screening Assays, Antitumor; Enzyme Inhibitors; Humans; Models, Molecular; Molecular Structure; Niacinamide; Quinazolinones; Structure-Activity Relationship; Tankyrases; 2 [4 (tert butyl)phenyl] 8 nitroquinazolin 4(3h)one; beta catenin; n [2 [4 (tert butyl)phenyl] 4 oxo 3,4 dihydroquinazolin 8 yl] 2,3 dihydroxypropanamide; nicotinamide; nicotinamide adenine dinucleotide adenosine diphosphate ribosyltransferase; quinazoline derivative; tankyrase; tankyrase 1; tankyrase 2; tankyrase inhibitor; unclassified drug; Wnt protein; antineoplastic agent; enzyme inhibitor; nicotinamide; quinazolinone derivative; tankyrase; TNKS2 protein, human; antiproliferative activity; Article; binding affinity; cancer inhibition; canonical Wnt signaling; COLO 320DM cell line; controlled study; crystal structure; crystallization; drug binding site; drug design; drug potency; drug selectivity; drug synthesis; enzyme inhibition; human; human cell; IC50; in vitro study; structure activity relation; substitution reaction; X ray crystallography; binding site; cell proliferation; chemical structure; chemistry; dose response; drug effect; drug screening; metabolism; molecular model; synthesis; tumor cell line",
    BIBTEX_ENTRY = "article",
    year = "2025",
    author = "Bosetti, Chiara and Kampasis, Dionysis and Brinch, Shoshy A. and Galera-Prat, Albert and Karelou, Maria and Dhakar, Saurabh S. and Alaviuhkola, Juho and Waaler, Jo and Lehtiö, Lari and Kostakis, Ioannis K.",
    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 pIC50 of 7.19, while the nitro-based compound EXQ-2d's pIC50 value is 7.86. Both analogues impact and attenuate the tankyrase-controlled WNT/β-catenin signaling with sub-micromolar IC50. 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. © 2025 The Authors",
    title = "Substitutions at the C-8 position of quinazolin-4-ones improve the potency of nicotinamide site binding tankyrase inhibitors",
    doi = "10.1016/J.EJMECH.2025.117397"
}