Efficacy of Providing the PI3K p110α Inhibitor BYL719 (Alpelisib) to Middle-Aged Mice in Their Diet

Abstract

BYL719 (alpelisib) is a small molecule inhibitor of PI3K p110α developed for cancer therapy. Targeted suppression of PI3K has led to lifespan extension in rodents and model organisms. If PI3K inhibitors are to be considered as an aging therapeutic, it is important to understand the potential consequences of long-term exposure, and the most practical way to achieve this is through diet administration. Here, we investigated the pharmacokinetics of BYL719 delivered in diet and the efficacy of BYL719 to suppress insulin signaling when administered in the diet of 8-month-old male and female mice. Compared to oral gavage, diet incorporation resulted in a lower peak plasma BYL719 (3.6 vs. 9.2 μM) concentration but similar half-life (~1.5 h). Consuming BYL719 resulted in decreased insulin signaling in liver and muscle within 72 h, and mice still showed impaired glucose tolerance and insulin sensitivity following 6 weeks of access to a diet containing 0.3 g/kg BYL719. However, consuming BYL719 did not affect food intake, body mass, muscle function (rotarod and hang time performance) or cognitive behaviors. This provides evidence that BYL719 has long-term efficacy without major toxicity or side effects, and suggests that administering BYL719 in diet is suitable for studying the effect of pharmacological suppression of PI3K p110α on aging and metabolic function.

Keywords: BYL-719; aging; glucose tolerance; insulin signaling; pharmacokinetics.

Figure 1

Experimental overview of long-term studies. GTT, glucose tolerance test; ITT, insulin tolerance test; NORT, novel object recognition test.

Figure 2

Pharmacokinetics (a,b) and changes in blood glucose (c) associated with delivering a single dose of BYL719 in the diet or via gavage in male mice. Plasma BYL719 (d) and food intake (e) of mice fed a control (Veh; vehicle) or BYL719 (BYL) containing diet for one week. Data are presented as mean ± SE, statistical analysis for (a,b) was by two-way repeated measures ANOVA with Sidak post-hoc, (d) by linear regression, and (e) by t-test. **** p < 0.001 vs. Veh at same time point. N = 6 per group for (a–d).

Figure 3

Gastrocnemius muscle and liver insulin receptor (IR) (a–d) and Akt (e–h) phosphorylation in male and female mice, following 72 h of receiving a control (Veh; vehicle) or BYL719 (BYL)-containing diet. Data are presented as mean ± SE, statistical analysis was by t-test, * p < 0.05, ** p < 0.01, *** p < 0.001 vs. Veh.

Figure 4

Body mass (a,b), plasma alanine aminotransferase (ALT) (c), HOMA-IR (d,e), and plasma non-esterified fatty acids (NEFA) (f) and triglycerides (g) of male and female middle-aged mice following 6 weeks of receiving a control- (Veh; vehicle) or BYL719 (BYL)-containing diet. Data are presented as mean ± SE, statistical analysis for was by two-way repeated measures ANOVA (a,b) and two-way ANOVA (d,e) with a Sidak post-hoc and/or t-test (c,f,g). ** p < 0.01, *** p < 0.001, **** p < 0.0001 vs. Veh, n = 6 per group for (a–d).

Figure 5

Glucose (a,b) and insulin tolerance tests (c,d), and blood glucose response to a meal challenge (e,f) of male and female middle-aged mice following 6 weeks of receiving a control- (Veh; vehicle) or BYL719 (BYL)-containing diet. Data are presented as mean ± SE, statistical analysis was by two-way repeated measures ANOVA with Sidak post-hoc. * p < 0.05, ** p < 0.01, *** p < 0.001 vs. Veh.

Figure 6

Rotarod (a) and hang time performance (b), novel and familiar object sniffing time (novel object test, c,d), time spent in inner and outer zone (e,f) and total movement distance (g,h) during open field test for middle-aged male and female mice after receiving a control- (Veh; vehicle) or BYL719 (BYL)-containing diet. Data are presented as mean ± SE, statistical analysis was by t-test (a,b,g,h) or two-way ANOVA with Sidak post-hoc (c–f).