D927 (DS11252927) is a small molecule glue and GLUT4 activator that facilitate RAS binding to PI3Kα, promotes glucose uptake in the absence of insulin, binds directly to p110α with dissociation constant (KD) of 5.6 uM.
D927 could increase the affinity of RAS binding to PI3Kα by ~500-fold.
D927 does not affect levels of the catalytic subunit (p110α) of PI3Kα.
D927 has no binding to PI3Kβ, PI3Kγ, PI3Kδ, or CRAF.
D927 activates the PI3Kα-AKT pathway, measured by increased phosphorylation of AKT (Ser473 and Thr308) and 70-kDa ribosomal protein S6 (p70S6) kinase (Thr389) in rat L6 myotubes, but has no substantial effect on the RAF-ERK1/2 pathway.
D927 increases phosphorylation of AKT (Ser473 and Thr308), p70S6 kinase (Thr389), and eukaryotic initiation factor 4E–binding protein 1 (4EBP1) (Thr37 or Thr46) in rat L6 myotubes.
D927 enhances the binding of all members of the RAS superfamily previously shown to bind p110α (KRAS4A, KRAS4B, RRAS, RRAS2, and MRAS) but not to RIT1, RAP1, RAP2, RHEB, or RAC2.
D927 (10 mg/kg, oral) exhibits in vivo insulin-mimicking effects on glucose homeostasis in animal models, acutely improves hyperglycemia independently of insulin secretion.
D927 promotes phosphorylation of AKT in the soleus, gastrocnemius, liver, heart, and white adipose tissue in normal C57BL/6j mice, similar to insulin.