Development of novel small molecules targeting mitochondrial and oxidative stress signaling pathways for pancreatic cancer therapy.

摘要

Pancreatic cancer is one of the deadliest cancers with a 5-year survival rate of 6%. Therapeutic options against this disease are limited and there is a critical unmet need for safe and efficacious treatments. Cancer cell metabolism and mitochondria provide unexplored targets for this disease. Here-in we describe the identification of a novel class of triphenylphosphonium salts, TP compounds, which target the mitochondria of cancer cells and display broad- spectrum anticancer properties. We examined the ability of our prototypical compound TP421 to inhibit the growth of pancreatic cancer cells and further investigated the molecular mechanisms by which it exerts its anticancer effects. TP421 showed sub-micromolar IC50 values in all the pancreatic cancer cell lines tested using MTT and colony formation assays. TP421 localized predominantly to mitochondria and induced G0/G1 arrest, ROS accumulation, and activation of several stress regulated kinases. Multiple caspases and PARP-1 cleavage were observed indicating an apoptotic response while LC3B-II and p62 were accumulated indicating inhibition of autophagy. Furthermore, TP421 induced de-phosphorylation of key signaling molecules involved in FAK mediated adhesion that correlated with inhibition of cell migration.;We also report the identification of a novel class of inhibitors of the essential base excision repair enzyme apurinic/apyrimidinic (AP) endonuclease (APE1). APE1 is a multi-faceted protein with an essential role in the base excision repair (BER) pathway. To protect cell genomes from potentially mutagenic or cytotoxic base damage arising from various exogenous or endogenous sources, APE1 nicks the DNA backbone 5' to AP sites generated primarily by lesion-specific glycosylases which remove damaged bases. Its implication in tumor development, progression and resistance has been confirmed in multiple cancers making it a viable target of intense investigation. Here we have designed and synthesized different classes of small molecule selective inhibitors of APE1's catalytic endonuclease function containing a 3-carbamoylbenzoic scaffold. Further structural modifications have been made with the aim of increasing activity and cytotoxicity of these inhibitors. Several of our compounds exhibited low micro-molar potencies towards inhibiting APE1's catalytic endonuclease function in vitro and thus represent novel classes of APE1 inhibitors worthy of further development.