title: Identification of NVP-TNKS656: the use of structure-efficiency relationships to generate a highly potent, selective, and orally active tankyrase inhibitor.
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.
authors.affiliation: Novartis Institutes for Biomedical Research, Inc., 250 Massachusetts Avenue, Cambridge, Massachusetts 02139, United States. michael.shultz@novartis.com
authors.forename: Michael D
authors.initials: MD
authors.lastname: Shultz
authors.forename: Atwood K
authors.initials: AK
authors.lastname: Cheung
authors.forename: Christina A
authors.initials: CA
authors.lastname: Kirby
authors.forename: Brant
authors.initials: B
authors.lastname: Firestone
authors.forename: Jianmei
authors.initials: J
authors.lastname: Fan
authors.forename: Christine Hiu-Tung
authors.initials: CH
authors.lastname: Chen
authors.forename: Zhouliang
authors.initials: Z
authors.lastname: Chen
authors.forename: Donovan N
authors.initials: DN
authors.lastname: Chin
authors.forename: Lucian
authors.initials: L
authors.lastname: Dipietro
authors.forename: Aleem
authors.initials: A
authors.lastname: Fazal
authors.forename: Yun
authors.initials: Y
authors.lastname: Feng
authors.forename: Pascal D
authors.initials: PD
authors.lastname: Fortin
authors.forename: Ty
authors.initials: T
authors.lastname: Gould
authors.forename: Bharat
authors.initials: B
authors.lastname: Lagu
authors.forename: Huangshu
authors.initials: H
authors.lastname: Lei
authors.forename: Francois
authors.initials: F
authors.lastname: Lenoir
authors.forename: Dyuti
authors.initials: D
authors.lastname: Majumdar
authors.forename: Etienne
authors.initials: E
authors.lastname: Ochala
authors.forename: M G
authors.initials: MG
authors.lastname: Palermo
authors.forename: Ly
authors.initials: L
authors.lastname: Pham
authors.forename: Minying
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authors.lastname: Pu
authors.forename: Troy
authors.initials: T
authors.lastname: Smith
authors.forename: Travis
authors.initials: T
authors.lastname: Stams
authors.forename: Ronald C
authors.initials: RC
authors.lastname: Tomlinson
authors.forename: B Barry
authors.initials: BB
authors.lastname: Touré
authors.forename: Michael
authors.initials: M
authors.lastname: Visser
authors.forename: Run Ming
authors.initials: RM
authors.lastname: Wang
authors.forename: Nigel J
authors.initials: NJ
authors.lastname: Waters
authors.forename: Wenlin
authors.initials: W
authors.lastname: Shao
mesh_terms: D000081:Acetamides / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D000284:Administration, Oral; D000818:Animals; D019540:Area Under Curve; D001682:Biological Availability; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000737:chemistry* / Q000494:pharmacology*; D051379:Mice; D008958:Models, Molecular; D011744:Pyrimidinones / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D038501:Tankyrases / Q000037:antagonists & inhibitors*
chemical_list: D000081:Acetamides; D004791:Enzyme Inhibitors; C584026:N-(cyclopropylmethyl)-2-(4-(4-methoxybenzoyl)piperidin-1-yl)-N-((4-oxo-4,5,7,8-tetrahydro-3H-pyrano(4,3-d)pyrimidin-2-yl)methyl)acetamide; D011744:Pyrimidinones; D038501:Tankyrases