title: Structure-efficiency relationship of [1,2,4]triazol-3-ylamines as novel nicotinamide isosteres that inhibit tankyrases.
abstract: Tankyrases 1 and 2 are members of the poly(ADP-ribose) polymerase (PARP) family of enzymes that modulate Wnt pathway signaling. While amide- and lactam-based nicotinamide mimetics that inhibit tankyrase activity, such as XAV939, are well-known, herein we report the discovery and evaluation of a novel nicotinamide isostere that demonstrates selectivity over other PARP family members. We demonstrate the utilization of lipophilic efficiency-based structure-efficiency relationships (SER) to rapidly drive the evaluation of this series. These efforts led to a series of selective, cell-active compounds with solubility, physicochemical, and in vitro properties suitable for further optimization.
authors.affiliation: Novartis Institutes for Biomedical Research Incorporated , 250 Massachusetts Avenue, Cambridge, Massachusetts 02139, United States.
authors.forename: Michael D
authors.initials: MD
authors.lastname: Shultz
authors.forename: Dyuti
authors.initials: D
authors.lastname: Majumdar
authors.forename: Donovan N
authors.initials: DN
authors.lastname: Chin
authors.forename: Pascal D
authors.initials: PD
authors.lastname: Fortin
authors.forename: Yun
authors.initials: Y
authors.lastname: Feng
authors.forename: Ty
authors.initials: T
authors.lastname: Gould
authors.forename: Christina A
authors.initials: CA
authors.lastname: Kirby
authors.forename: Travis
authors.initials: T
authors.lastname: Stams
authors.forename: Nigel J
authors.initials: NJ
authors.lastname: Waters
authors.forename: Wenlin
authors.initials: W
authors.lastname: Shao
mesh_terms: D000588:Amines / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D004797:Enzyme-Linked Immunosorbent Assay; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D013329:Structure-Activity Relationship; D038501:Tankyrases / Q000037:antagonists & inhibitors*; D014230:Triazoles / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D000588:Amines; D014230:Triazoles; D038501:Tankyrases