Decoding the transcriptional regulation of therapeutic responses
The body’s defense system is finely tuned to detect, destroy, or export endogenous or foreign toxic substances. While this system has obvious protective benefits, it can also contribute to treatment failure by increasing drug resistance and toxicity. Our laboratory uses promiscuous nuclear receptors as a model to investigate the transcriptional regulation of response to therapeutics. Using small molecules to degrade these receptors, we are able to control their role in drug metabolism to help improve clinical intervention.
Our laboratory develops and uses small molecules targeting pregnane X receptor (PXR), a xenobiotic receptor that essentially acts as a switch of the garbage disposal in cells. PXR promiscuously binds to many toxic compounds and elevates the levels of enzymes that destroy these toxic compounds. The ligand promiscuity and structural flexibility of PXR have historically hampered the development of chemical modulators, the lack of which has been critical barrier to investigating its transcriptional regulation. Our research aims to employ small molecules to inhibit and control PXR and, in turn, decrease drug resistance and prevent toxicity.
To tackle the challenging problem of controlling the transcription factor PXR, our laboratory integrates model systems and chemical biology as well as high-throughput technologies. These approaches led us to develop the first specific PXR antagonist/inverse agonist (SPA70), and its analogs and derivatives with varying cellular activities – activating, inhibiting, or blocking. These mechanistically characterized novel chemical modulators enable us to understand how to precisely control the transcriptional activity of PXR in regulating drug metabolism.
In addition, the PXR antagonist/inverse agonist SPA70 has been used to attenuate PXR-mediated liver injury in an animal model, supporting the feasibility of pharmacologic inhibition of PXR as a remedy for drug toxicity.
Dr. Taosheng Chen received his BS and MS degrees from Fudan University in Shanghai and his PhD from the University of Vermont guided by Janet Kurjan. He completed his post-doctoral training under Michael Weber at the University of Virginia. Having spent time in the pharmaceutical industry, Dr. Chen brings his expertise in drug discovery and development to St. Jude where he serves as Director of the High Throughput Bioscience Center. Dr. Chen has built a lab of chemists and biologists in order to answer questions about drug toxicity, drug resistance, and human disease.
Multidisciplinary team of biologists and chemists