Identification of NVP-TNKS656: The Use of Structure鈥揈fficiency Relationships To Generate a Highly Potent, Selective, and Orally Active Tankyrase Inhibitor

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• 作者：Michael D. Shultz ; Atwood K. Cheung ; Christina A. Kirby ; Brant Firestone ; Jianmei Fan ; Christine Hiu-Tung Chen ; Zhouliang Chen ; Donovan N. Chin ; Lucian DiPietro ; Aleem Fazal ; Yun Feng ; Pascal D. Fortin ; Ty Gould ; Bharat Lagu ; Huangshu Lei ; Francois Lenoir ; Dyuti Majumdar ; Etienne Ochala ; M. G. Palermo ; Ly Pham ; Minying Pu ; Troy Smith ; Travis Stams ; Ronald C. Tomlinson ; B. Barry Tour茅 ; Michael Visser ; Run Ming Wang ; Nigel J. Waters ; Wenlin Shao
• 刊名：Journal of Medicinal Chemistry
• 出版年：2013
• 出版时间：August 22, 2013
• 年：2013
• 卷：56
• 期：16
• 页码：6495-6511
• 全文大小：669K
• 年卷期：v.56,no.16(August 22, 2013)
• ISSN：1520-4804

文摘

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.