1. Academic Validation
  2. Efficacy of Providing the PI3K p110α Inhibitor BYL719 (Alpelisib) to Middle-Aged Mice in Their Diet

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

  • Biomolecules. 2021 Jan 25;11(2):150. doi: 10.3390/biom11020150.
Christopher P Hedges 1 2 Jordi Boix 3 Jagdish K Jaiswal 2 4 Bhoopika Shetty 1 Peter R Shepherd 2 5 Troy L Merry 1 2
Affiliations

Affiliations

  • 1 Discipline of Nutrition, School of Medical Sciences, University of Auckland, Auckland 1023, New Zealand.
  • 2 Maurice Wilkins Centre for Molecular Biodiscovery, University of Auckland, Auckland 1023, New Zealand.
  • 3 Centre for Brain Research, University of Auckland, Auckland 1023, New Zealand.
  • 4 Auckland Cancer Society Research Centre, University of Auckland, Auckland 1023, New Zealand.
  • 5 Molecular Medicine and Pathology, School of Medical Sciences, University of Auckland, Auckland 1023, New Zealand.
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.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-15244
    99.95%, PI3Kα抑制剂