ABSTRACT
Lipid phosphatase SH2 domain-containing inositol 5'-phosphatase 2 (SHIP2) plays an important role in the regulation of insulin signaling. In this report, we identified AS1938909, a novel small-molecule SHIP2 inhibitor. AS1938909 showed potent inhibition of SHIP2 (Ki=0.44 microuM) and significant selectivity over other related phosphatases. Further, AS1938909 increased Akt phosphorylation, glucose consumption, and glucose uptake in L6 myotubes. Treatment of L6 myotubes with SHIP2 inhibitors for 48 h significantly induced expression of GLUT1 mRNA, but not that of GLUT4. These results suggest that pharmacological inhibition of SHIP2 activates glucose metabolism due, at least in part, to up-regulation of GLUT1 gene expression.
Subject(s)
Enzyme Inhibitors/pharmacology , Glucose Transporter Type 1/genetics , Glucose/metabolism , Muscle Fibers, Skeletal/drug effects , Muscle Fibers, Skeletal/metabolism , Phosphoric Monoester Hydrolases/antagonists & inhibitors , Up-Regulation/drug effects , Animals , Biological Transport/drug effects , Cell Line , Drug Evaluation, Preclinical , Mice , Phosphatidylinositol-3,4,5-Trisphosphate 5-Phosphatases , Phosphorylation/drug effects , Proto-Oncogene Proteins c-akt/metabolism , RNA, Messenger/genetics , RNA, Messenger/metabolism , RatsABSTRACT
The synthesis and biological activity of novel 1-phenylsulfonyl-4- phenylsulfonylaminopyrrolidine analogues are described. All compounds were produced through modification of the substituent formally corresponding to the 1,3-dioxane ring system and the omega-octenol side chain of thromboxane A(2) (TXA(2)), in reference to the structure of Daltroban. Several compounds were found to be potent TXA(2) receptor antagonists. Compound 51a was the most effective inhibitor of 9,11-epoxymethano PGH(2) (U-46619)-induced rat aortic strip contraction (IC(50)=0.48 nM).
