877972-04-8Relevant academic research and scientific papers
Structure-activity relationships of 2-arylquinazolin-4-ones as highly selective and potent inhibitors of the tankyrases
Nathubhai, Amit,Haikarainen, Teemu,Hayward, Penelope C.,Mu?oz-Descalzo, Silvia,Thompson, Andrew S.,Lloyd, Matthew D.,Lehti?, Lari,Threadgill, Michael D.
supporting information, p. 316 - 327 (2016/05/19)
Tankyrases (TNKSs), members of the PARP (Poly(ADP-ribose)polymerases) superfamily of enzymes, have gained interest as therapeutic drug targets, especially as they are involved in the regulation of Wnt signalling. A series of 2-arylquinazolin-4-ones with varying substituents at the 8-position was synthesised. An 8-methyl group (compared to 8-H, 8-OMe, 8-OH), together with a 4′-hydrophobic or electron-withdrawing group, provided the most potency and selectivity towards TNKSs. Co-crystal structures of selected compounds with TNKS-2 revealed that the protein around the 8-position is more hydrophobic in TNKS-2 compared to PARP-1/2, rationalising the selectivity. The NAD+-binding site contains a hydrophobic cavity which accommodates the 2-aryl group; in TNKS-2, this has a tunnel to the exterior but the cavity is closed in PARP-1. 8-Methyl-2-(4-trifluoromethylphenyl)quinazolin-4-one was identified as a potent and selective inhibitor of TNKSs and Wnt signalling. This compound and analogues could serve as molecular probes to study proliferative signalling and for development of inhibitors of TNKSs as drugs.
TANKYRASE INHIBITORS
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Page/Page column 104, (2014/06/24)
The present invention relates to a compound of formula I wherein X is C(R6) or N, Y is C or N, and ring A, ring B, R1 and R2 have the meanings defined herein, provided that when ring B is carbocyclic, X is C(R6); or a pharmaceutically acceptable salt or solvate thereof. The compounds are tankyrase-1 and tankyrase-2 inhibitors and are useful in the treatment of a number of conditions, including cancer.
Identification of NVP-TNKS656: The use of structure-efficiency relationships to generate a highly potent, selective, and orally active tankyrase inhibitor
Shultz, Michael D.,Cheung, Atwood K.,Kirby, Christina A.,Firestone, Brant,Fan, Jianmei,Chen, Christine Hiu-Tung,Chen, Zhouliang,Chin, Donovan N.,Dipietro, Lucian,Fazal, Aleem,Feng, Yun,Fortin, Pascal D.,Gould, Ty,Lagu, Bharat,Lei, Huangshu,Lenoir, Francois,Majumdar, Dyuti,Ochala, Etienne,Palermo,Pham, Ly,Pu, Minying,Smith, Troy,Stams, Travis,Tomlinson, Ronald C.,Touré, B. Barry,Visser, Michael,Wang, Run Ming,Waters, Nigel J.,Shao, Wenlin
, p. 6495 - 6511 (2013/09/23)
Tankyrase 1 and 2 have been shown to be redundant, druggable nodes in the Wnt pathway. As such, there has been intense interest in developing agents suitable for modulating the Wnt pathway in vivo by targeting this enzyme pair. By utilizing a combination of structure-based design and LipE-based structure efficiency relationships, the core of XAV939 was optimized into a more stable, more efficient, but less potent dihydropyran motif 7. This core was combined with elements of screening hits 2, 19, and 33 and resulted in highly potent, selective tankyrase inhibitors that are novel three pocket binders. NVP-TNKS656 (43) was identified as an orally active antagonist of Wnt pathway activity in the MMTV-Wnt1 mouse xenograft model. With an enthalpy-driven thermodynamic signature of binding, highly favorable physicochemical properties, and high lipophilic efficiency, NVP-TNKS656 is a novel tankyrase inhibitor that is well suited for further in vivo validation studies.
