Akt is a serine threonine kinase that plays a pivotal role in a diverse set of signaling cascades involved read FAQ in the regulation of cell survival, cell growth, glucose metabolism, cell motility and angiogenesis. Akt is activated when phosphorylated and activated Akt normally promotes cell survival by inactivating the components of apoptotic stimuli. However, under Inhibitors,Modulators,Libraries oxi dative stress conditions the pro survival function of Akt can be overridden and function in a pro apoptotic role. Chemotherapeutic agents that induce oxida tive stress and produce heightened cellular levels of ROS therefore have the potential to selectively induce apoptosis in Akt activated cancer cells. Tumor cell apoptosis can be induced through oxidative stress by reducing or inhibiting cellular antioxidants.

Glutathione is the primary intracellular antioxidant and plays a key role in modulating Inhibitors,Modulators,Libraries tumor cell proliferation as well as the resist ance of tumors to many chemotherapeutic drugs. GSH depletion causes growth inhibition in many Inhibitors,Modulators,Libraries types of cancers including pancreatic cancer. In an animal model, GSH depletion was found to sensitize melanoma cancer cells to combination chemotherapy and eliminate metastatic disease. Nitric oxide donating acetylsalicylic acid is a promising anticancer prodrug ester that depletes GSH and promotes oxidative stress induced apoptosis. NO ASA is thought to exert its anticancer effects by an esterase catalyzed release of an electrophile quinone methide intermediate that selectively reacts with and depletes intracellular GSH.

We have hypothe sized that a hybrid ester prodrug containing the Inhibitors,Modulators,Libraries QM generating moiety that is selectively hydrolyzed and activated by oxidized protein hydrolase will deplete intracellular GSH and promote oxidative stress induced apoptosis in cancer cells by a mechanism similar to that of NO ASA, i. e, release of a QM depleting intermediate. OPH, also called acylamino acid releasing enzyme, is a serine esterase protease that we found to be over expressed in some tumorigenic prostate cell lines. Moreover, histological data in the Human Protein Atlas shows that OPH can be strongly expressed in cases of colorectal, breast, prostate, ovarian, endometrial and liver cancers. We have previously found that OPH selectively catalyzes the hydrolysis of chiral naphthyl N acetylalaninate Inhibitors,Modulators,Libraries esters with a preference for the S isomer. A novel prodrug S NPAA, was previously advanced as a plausible antican cer prodrug candidate based on its in silico binding affin ity to the active site of 3 dimensional models of both rat and human OPH as well as its in vitro ability to deplete GSH when activated by rat OPH. S NPAA is composed of an during N acetylalaninate moiety recognized by OPH and the QM generating moiety of NO ASA.