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.
Current treatments for schizophrenia, which include typical and atypical antipsychotic drugs (APDs), are limited in efficacy, even with regard to treatment of psychosis, and often cause serious side effects. For the typical APDs, these are motor symptoms, including tardive dyskinesia, prolactin elevations and weight gain. The currently available 5-HT2C agonists, alone or as augmentation of typical and atypical APDs, have shown robust activity as antipsychotics and cognitive enhancers, without compromising motor function. In animal models, 5-HT2C agonists can modulate hippocampal theta rhythms that play a role in learning, memory and emotional behaviors. A major unmet need is drugs to robustly improve psychosis and cognitive impairment of schizophrenia (CIS). We have discovered that 5-HT2C agonists, including the natural products alstonine and serpentine, can potentiate the ability of atypical APDs to ameliorate the cognitive deficit produced by sub-chronic PCP in rats and mice. Thus, 5-HT2C receptor agonism is a potential novel way to treat positive symptoms and CIS. Ultimately, this new knowledge will drive the development of new treatments for the psychosis and cognitive impairment of schizophrenia without the debilitating side effects of current treatments.
Mellpaladines A and B are guanidine alkaloids with a unique dithiol ketal isolated from a Palauan colonial tunicate of the family Didemnideae in 2016. These cyclized dopamine analogues each contain a dithiol ketal moiety, differentiating them from all other natural products described in the literature to date. The mellpaladines exhibit potent and selective 5HT5A antagonism, rendering these scaffolds highly desirable neuropharmacological probes. The role of the 5-HT5 class of receptors in CNS function is poorly understood due to the limited availability of selective antagonists. However, 5-HT5A receptors could represent targets of opportunity for mood disorders, and a number of studies have demonstrated a correlation between 5HT5A polymorphisms and schizophrenia.
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.
Acute lymphoblastic leukemia (ALL) is the most common hematological childhood cancer and the most frequent cause of cancer-related death before the age of 20. Nearly one quarter of pediatric patients exhibit resistance to current treatments. Targeting key molecular signaling pathways that facilitate this resistance could drastically reduce mortality in cases of therapy-resistant ALL. Towards this end, we are working to develop a novel small molecule inhibitor of MEK7, a signaling protein and key mediator of chemoresistance in T-cell ALL. In doing so, we hope to contribute towards the first targeted therapy for this deadly childhood disease.
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. Furthermore, telomerase has demonstrated to have multiple oncogenic and tumorigenic roles outside of its role in telomere maintenance, demonstrating the potential for telomerase as a therapeutic target in numerous cancer types. 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.