Tankyrase Inhibition Causes Reversible Intestinal Toxicity in Mice with a Therapeutic Index < 1.

摘要: Activated Wnt/β-catenin signaling is frequently associated with colorectal cancer. Wnt inhibitors, including tankyrase are being explored as potential anticancer agents. also critical for intestinal tissue homeostasis, and inhibitors have been shown to cause toxicity in mice by affecting stem cells. This study sought characterize the of reversibility, assess their therapeutic index. Novel inhibitor G-631 caused dose-dependent a index < 1 after 14 days dosing mice. At tolerated subtherapeutic dose level, was composed enteritis characterized villus blunting, epithelial degeneration, inflammation, which fully reversed recovery. Doubled exposure showed weak antitumor activity xenograft cancer model but more severe multifocal-regionally extensive necrotizing ulcerative leading morbidity or moribundity some animals. only partially recovery, evidence crypt regeneration, mildly blunted villi, and/or scarring association chronic inflammation submucosa. Therefore, clinical utility likely limited on-target