Our bioorganic/drug discovery program is focused on the development of novel agents for the treatment and prevention of advanced cancer. Our previous work has focused our efforts on the total synthesis and derivatization of flavanoid natural products, which are known to have potent antiproliferative and antioxidant activity against a number of cancer lines. We have used rational design and fragment-based diversification approaches to access potent and selective analogs of natural products which can be screened in relevant in vitro and in vivo models of late-stage cancer. This has ultimately allowed us to identify important small molecules that can act as both chemotherapeutic agents and effective tools to improve our understanding of the processes that drive cancer progression. These efforts have led to the development of a potent small molecule inhibitor of prostate cancer metastasis, KBU2046, which has shown promise in preclinical animal models and is currently being studied for its potential in human subjects. Through this collaborative research we have discovered that MEK4 plays a critical role in prostate cancer metastasis.
Prostate cancer (PCa) is the most common cancer in American men and the 5-year survival rate for stage IV PCa is <30%, with over 80% of all cancer deaths resulting from the formation of distant metastases. Targeting key molecular processes that regulate metastasis could significantly improve advanced PCa mortality by affecting uniform steps early in the metastatic process that take place in the primary organ. We are creating new chemical probes to enhance our understanding of MEK4 function in human PCa cell invasion and metastasis, which shall ultimately catalyze the development of the first generation of antimetastatic agents for prostate cancer.
Telomerase is a ribonucleoprotein enzyme that plays an important role in the immortalization of cancer cells. Normally, the shortening of telomeres during successive rounds of DNA replication eventually leads to senescence, limiting the proliferative potential of eukaryotic cells. While telomerase is not activated in most normal somatic cells, 80-90% of primary tumor cells show telomerase activity in humans. Inspired by the natural product chrolactomycin, a reported telomerase inhibitor, we have undertaken a program to design, synthesize, and evaluate novel small molecule inhibitors of telomerase.