Identification of NVP-TNKS656: the use of structure-efficiency relationships to generate a highly potent, selective, and orally active tankyrase inhibitor
| Autor: | Atwood K. Cheung, Minying Pu, Travis Stams, Donovan N. Chin, Dyuti Majumdar, Pascal D. Fortin, Francois Lenoir, Lei Huangshu, Pham Ly Luu, Run Ming Wang, Christina A. Kirby, Etienne Ochala, Aleem Fazal, Dipietro Lucian, Bharat Lagu, Chen Christine Hiu-Tung, Yun Feng, Palermo Mark G, Wenlin Shao, Ronald Tomlinson, Nigel J. Waters, Michael Shultz, Brant Firestone, Zhouliang Chen, Jianmei Fan, Ty Gould, Michael Scott Visser, B. Barry Touré, Troy Smith |
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| Rok vydání: | 2013 |
| Předmět: |
chemistry.chemical_classification
Models Molecular Tankyrases Dihydropyran Druggability Antagonist Wnt signaling pathway Administration Oral Biological Availability Pyrimidinones Tankyrase-1 chemistry.chemical_compound Mice Structure-Activity Relationship Enzyme chemistry Biochemistry In vivo Lipophilic efficiency Area Under Curve Drug Discovery Acetamides Molecular Medicine Animals Enzyme Inhibitors |
| Zdroj: | Journal of medicinal chemistry. 56(16) |
| ISSN: | 1520-4804 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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