ASP4132 is an Orally Active AMPK Activator
Posted On 2020-06-23
Adenosine monophosphate (AMP)-activated protein kinase (AMPK) is an enzyme that plays a role in cellular energy homeostasis. Specifically, it is important in largely to activate glucose and fatty acid uptake and oxidation when cellular energy is low. Besides, AMP or adenosine diphosphate (ADP) levels increase during metabolic stress such as during malnutrition, hypoxia, and muscle contraction. Moreover, AMPK responds to intracellular AMP concentration, which is the result of reduced adenosine levels triphosphate (ATP). In response to an increase in AMP/ATP ratio, AMPK shuts down ATP consumption pathways, such as gluconeogenesis and fatty acid synthesis. Furthermore, AMPK activates ATP production pathways, including fatty acid oxidation and glycolysis. AMPK activation is an attractive strategy for the treatment of human tumors. Meanwhile, the increased AMPK expression and activity are linked to improved survival in many human tumors. ASP4132 is an orally active, potent AMPK activator with anti-cancer activity.
ASP4132 is an orally active, potent AMPK activator with anti-cancer activity.
But, how does ASP4132 protect against cancer cells via AMPK? Let’s discuss it in detail. First of all, ASP4132 is an orally active, potent AMPK activator with an EC50 of 18 nM. Importantly, ASP4132 has anti-cancer activity and makes tumor regression in breast cancer xenograft mouse models.
In addition, ASP4132 shows comparable cell growth inhibitory (IC50=0.014 μM) activity against MDA-MB-453 breast cancer cells. Nonetheless, ASP4132 shows relatively weak antiproliferative activity against SK-BR-3 (IC50>3 μM). Particularly, ASP4132 causes tumor growth inhibition and regression. The tumor growth inhibition (TGI) rate was 29% at 1 mg/kg, and the tumor regression rate was 26%, 87%, and 96% at 2, 4, and 8 mg/kg, respectively. Obviously, ASP4132 has a T1/2 of 3.6 hours, a CLtot of 19 mL/min•kg, and a Vss of 4.6 L/kg for rats for IV. ASP4132 is stable in human liver microsomes (HLM CLint, vitro=61 mL/min/kg).
All in all, ASP4132 is an orally active, potent AMPK activator with anti-cancer activity.
Kazuyuki Kuramoto, et al. Bioorg Med Chem. 2020 Mar 1;28(5):115307.