Abstract
Considering the common occurrence of the adverse cardiovascular events caused by PI3K inhibitors in clinical trials, a comprehensive assessment of the cardiotoxicity of promising PI3K inhibitor candidates for their potential clinical translation is of great importance. Based on our previous studies of the 7-azaindazole-based PI3K inhibitors, in this work, we report a potential novel PI3K inhibitor, N-(2-chloro-5-(3-(pyridin-4-yl)-1H-pyrazolo[3,4-b]pyridin-5-yl)pyridin-3-yl)-4-fluorobenzenesulfonamide (FD274), with low cardiotoxicity in mice. FD274 exhibited minimal adverse effects in inducing cardiac dysfunction, oxidative stress and cardiac injury when compared to the positive control FD268, a bioisostere of FD274. Additionally, western blot analyses suggested that the minimal adverse effects of FD274 could be related to the preservation of the activity of the antioxidant pathway protein Nrf2. In contrast, the downregulation of Nrf2 as well as the upregulation of NADPH oxidase and the apoptosis-related proteins resulted in the cardiotoxicity of FD268. Finally, we confirmed the low cardiotoxicity of FD274 after the 20-day treatment process in the HL-60 xenograft mice model. Our results confirmed the low cardiotoxicity of FD274 which deserves further development.