9rqq
Tankyrase 2 in complex with an inhibitor
Structural highlights
FunctionTNKS2_HUMAN Poly-ADP-ribosyltransferase involved in various processes such as Wnt signaling pathway, telomere length and vesicle trafficking. Acts as an activator of the Wnt signaling pathway by mediating poly-ADP-ribosylation of AXIN1 and AXIN2, 2 key components of the beta-catenin destruction complex: poly-ADP-ribosylated target proteins are recognized by RNF146, which mediates their ubiquitination and subsequent degradation. Also mediates poly-ADP-ribosylation of BLZF1 and CASC3, followed by recruitment of RNF146 and subsequent ubiquitination. Mediates poly-ADP-ribosylation of TERF1, thereby contributing to the regulation of telomere length. May also regulate vesicle trafficking and modulate the subcellular distribution of SLC2A4/GLUT4-vesicles.[1] [2] [3] [4] Publication Abstract from PubMedA series of fused isoquinolinone/triazole hybrids were designed and prepared applying a unified versatile synthetic strategy. This practically involved three steps, a novel one-pot CuAAc "click" reaction-iodination process, an amidation and a copper-catalyzed intramolecular Ullmann cyclization and was found to be applicable for a variety of substitutions patterns on the main framework. Some of those synthesized hybrids were tested for selected ADP-ribosyltransferases and found to display nanomolar potency against TNKS2, whereas selectivity was also observed in comparison to other tested PARPs. The SAR studies divulged key structural features which are responsible for this selectivity. Moreover, the identification of the binding site of those selective derivatives using X-ray crystallography revealed that they are accommodated in the nicotinamide binding subsite while certain groups extend toward a hydrophobic pocket unique to tankyrases. Discovery of Fused Isoquinolinone/Triazole as a Scaffold for Tankyrase and PARP Inhibition.,Ouzounthanasis KA, Bosetti C, Alaviuhkola J, Dhakar SS, Mantzourani C, Kokotou MG, Kanetidis D, Lehtio L, Koumbis AE J Med Chem. 2026 Jan 8;69(1):330-351. doi: 10.1021/acs.jmedchem.5c02481. Epub , 2025 Dec 27. PMID:41455111[5] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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