The Chen Lab studies: i) Chemical modulation of transcription; ii) Signal crosstalk among transcription factors; and iii) Selective inhibition of highly homologous enzymes. We take a hypothesis-driven and technology-enabled multidisciplinary approach to develop chemical probes and investigate biological mechanisms. Particularly we use the promiscuous xenobiotic nuclear receptors (PXR and CAR) as models to investigate the transcription networks that regulate therapeutic responses. PXR and CAR regulate the detoxification system (e.g., by transcriptionally controlling CYP3A4 and CYP3A5—drug-metabolizing enzymes that metabolize more than 50% of clinical drugs), the dysregulation of which contributes to drug toxicity and drug resistance. We have developed the first selective PXR antagonist (Nat Commun 8:741, 2017); established that PXR and CAR form an unexpected heterodimer (Nucleic Acids Res 50(6):3254-3275, 2022); revealed a mechanism that expands PXR’s ligand binding pocket to reduce ligand’s binding affinity (Proc Natl Acad Sci U S A. 120: e2217804120, 2023); and discovered the first CYP3A5-selective inhibitor and its structural basis (J Am Chem Soc 143:18467, 2021). Our goal is design therapeutic approaches to overcome drug toxicity, drug resistance and tumorigenesis in cellular and animal models.
The Chen Lab provides a unique training environment: in addition to basic mechanistic biology research, the postdoctoral fellow will learn and gain experience in small molecule drug discovery from target validation, chemical probe discovery to preclinical mechanistic studies. The postdoctoral fellow will collaborate with structural biologists and medicinal chemists in the Chen Lab, and have opportunities to work with the High Throughput Bioscience (HTB) Center (directed by Dr. Chen) (https://www.stjude.org/research/departments/chemical-biology-therapeutics/high-throughput-biosciences.html) on target validation, assay development, and compound or siRNA screening. Former Chen Lab postdocs have landed jobs as Assistant Professors in Universities, Senior Scientists in Pharmaceutical Companies, or Staff Scientists at St. Jude.