Formylchromone derivatives as irreversible and selective inhibitors of human protein tyrosine phosphatase 1B. Kinetic and modeling studies.

A series of formylchromone derivatives were synthesized as PTP1B inhibitors and some of them were potent against PTP1B with IC50 values as low as 1.0 microM. They exhibited remarkable selectivity for PTP1B over other human PTPases. Kinetic studies revealed that formylchromone derivatives are irreversible and active site-directed inhibitors. Molecular modeling study identified the orientation of the inhibitor bound at the active site of PTP1B.

Aurintricarboxylic acid translocates across the plasma membrane, inhibits protein tyrosine phosphatase and prevents apoptosis in PC12 cells.

Aurintricarboxylic acid (ATA) prevents apoptosis in a diverse range of cell types including PC12 cells. It is known to stimulate tyrosine phosphorylation of signaling proteins including Shc proteins, phosphatidylinositol 3-kinase, phospholipase C-g and mitogen-activated protein kinases (MAPKs). However, it has been unclear how ATA increases the phosphorylation of these proteins as it was believed to be membrane impermeable. We found that ATA translocates across the plasma membrane of PC12 cells and have confirmed that it is a potent inhibitor of protein tyrosine phosphatases (PTP ases). Other PTPase inhibitors also prevented apoptosis independent of ATA. These observations indicate that ATA exerts its anti-apoptotic effect on PC12 cells at least in part by inhibiting certain PTPase(s).

Evans Blue and other dyes as protein tyrosine phosphatase inhibitors.

Commonly used dyes including Evans Blue and Trypan Blue were examined for their inhibitory activities against protein tyrosine phosphatases (PTPases), all of them showed inhibition of PTPases with different potencies. Of the 13 dyes tested, four exhibited IC(50) value of less than 10 microM, Evans Blue lowest IC(50) of 1.3 microM against PTP1B. Care must be taken in the use of dyes for clinical or biochemical experiments to avoid unwanted side effects. Some of the low molecular weight dyes might be useful as lead compounds for the development of potent and selective PTPase inhibitors.

Formylchromone derivatives as a novel class of protein tyrosine phosphatase 1B inhibitors.

Formylchromone inhibits a human protein tyrosine phosphatase PTP1B with a IC(50) value of 73 microM. The chemical reactivity of formylchromone was adjusted by substitution at various positions of the formylchromone skeleton. In an initial assessment of the structure-activity relationship, the most potent inhibitor showed an IC(50) of 4.3 microM against PTP1B and strong or medium selectivity against other human PTPases, LAR and TC-PTP. This compound, however, was not selective against microbial PTPases, YPTP1 and YOP. The potency and selectivity of the formylchromone derivatives expecting further improvements provides a novel pharmacophore for the design of drugs for the treatment of type 2 diabetes and obesity.