Two areas of our research are briefly described below:
1. Small Molecule Inhibitors of CREB-mediated Gene Transcription as Anticancer Agents.
Cyclic-AMP (cAMP) response element binding protein (CREB) is a transcription factor activated by phosphorylation at Ser133 by mitogen- and stress-activated protein kinases including PKB/Akt, p90RSK, MAPK and PKA. The phosphorylated CREB (p-CREB) then binds the mammalian transcription co-activator, CREB-binding protein (CBP), to further recruit other transcriptional machinery to initiate CREB-dependent gene transcription. CREB serves a variety of biological functions including cellular proliferation, differentiation and adaptive responses. Recent studies have revealed that CREB is overexpressed in many different cancer cells and participates in the regulation of immortalization and transformation of cancer cells. This pleiotropic factor represents a great target for cancer therapy because it is a focal point of many signaling pathways over-activated in cancer cells. We recently discovered a small molecule inhibitor of CREB-mediated gene transcription, naphthol AS-E, potently inhibit cancer cell proliferation and induce apoptosis in a variety of different cancer cells. Currently, we are investigating its mechanism of action and structure-activity relationships to design better anticancer drugs.
2. Design and Synthesis of Small Molecules for Cancer Cell Specific Gene Delivery.
Gene therapy represents a promising treatment for cancer. Successful gene therapy requires a safe and efficient vehicle to deliver a gene of interest, either in the form of DNA or RNA, into the cancer cells. Current methods of gene delivery rely heavily on viral vectors because of their high delivery efficiency. However, safety issues from viral vectors continue to plague gene therapy. We are interested in small molecule-based non-viral vectors as targeted gene delivery vehicles. The compounds are designed to bind and condense nucleic acids. In addition, a cancer cell specific ligand will be displayed on these compounds, which would potentially direct the gene delivery complexes only to the cancer cells. This targeted delivery complex would dramatically improve gene therapy efficacy while minimizing side effects.