8S4W

Tankyrase 2 in complex with a quinazolin-4-one inhibitor

This is a non-PDB format compatible entry.

Summary for 8S4W

• Entry DOI: 10.2210/pdb8s4w/pdb
• Descriptor: Poly [ADP-ribose] polymerase tankyrase-2, (2~{R})-~{N}-[2-(4-~{tert}-butylphenyl)-4-oxidanylidene-3~{H}-quinazolin-8-yl]-2,3-bis(oxidanyl)propanamide, ZINC ION, ... (6 entities in total)
• Functional Keywords: inhibitor, transferase, tankyrase 2
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 2
• Total formula weight: 25485.05

Authors

Bosetti, C.,Lehtio, L. (deposition date: 2024-02-22, release date: 2025-03-05, Last modification date: 2025-03-26)

Primary citation

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

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: 39983556
DOI: 10.1016/j.ejmech.2025.117397

Experimental method

X-RAY DIFFRACTION (2.12 Å)