Shultz, Michael, Kirby, Christina, Firestone, Brant, Fan, Jianmei, Chen, Christine, Chen, Zhuoliang, Cheung, Atwood, Chin, Donovan, DiPietro, Lucian, Fazal, Aleem, Feng, Yun, Fortin, Pascal, Gould, Ty, Huangshu, Lei, Lenoir, Francois, Majumdar, Dyuti, Ochala, Etienne, Palermo, Mark, Pham, Ly, Pu, Minying, Smith, Troy, Tomlinson, Ronald, Toure, Bakary-Barry, Visser, Michael, Wang, Run-Ming, Waters, Nigel and Shao, Wenlin (2013) Identification of NVP-TNKS656: The use of structure-efficiency relationships to generate a highly potent, selective, and orally active tankyrase inhibitor. Journal of Medicinal Chemistry, 56 (16). pp. 6495-6511. ISSN 0022-2623

Abstract

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. © 2013 American Chemical Society.

Item Type:	Article
Additional Information:	1. Disclosure of TNKS656 part of external collaborations 2. NVP numbers and structures in experimental section are for internal review and will be removed prior to journal submission
Date Deposited:	30 Nov 2017 00:45
Last Modified:	25 Jan 2019 00:46
URI:	https://oak.novartis.com/id/eprint/9676