9feg

PARP15 in complex with a quinazolin-4-one inhibitor

spinqualitylabelsall models 9feg, resolution 1.75Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 9feg is a 2 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 1.75Å Ligands: A1H44, DMS, MPD Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function PAR15_HUMAN Transcriptional repressor. Has ADP-ribosyltransferase activity. Publication Abstract from PubMed 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(50) of 7.19, while the nitro-based compound EXQ-2d's pIC(50) value is 7.86. Both analogues impact and attenuate the tankyrase-controlled WNT/beta-catenin signaling with sub-micromolar IC(50). 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. Substitutions at the C-8 position of quinazolin-4-ones improve the potency of nicotinamide site binding tankyrase inhibitors.,Bosetti C, Kampasis D, Brinch SA, Galera-Prat A, Karelou M, Dhakar SS, Alaviuhkola J, Waaler J, Lehtio L, Kostakis IK Eur J Med Chem. 2025 Apr 15;288:117397. doi: 10.1016/j.ejmech.2025.117397. Epub , 2025 Feb 15. PMID:39983556 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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