Document Report Card

ID: ALA2424545

Journal: J Med Chem

Title: Structure-efficiency relationship of [1,2,4]triazol-3-ylamines as novel nicotinamide isosteres that inhibit tankyrases.

Authors: Shultz MD, Majumdar D, Chin DN, Fortin PD, Feng Y, Gould T, Kirby CA, Stams T, Waters NJ, Shao W.

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.

CiteXplore: 23879431

DOI: 10.1021/jm400826j