The Chen Lab (https://www.stjude.org/research/labs/chen-lab-taosheng.html) is seeking a Postdoctoral Research Associate to work in a multidisciplinary team to study the regulation of PXR and CAR, or CYP3A4 and CYP3A5, by characterizing novel chemical probes (i.e., small molecule inhibitors or degraders) in biochemical/biophysical, cellular and animal models.

Drug toxicity and resistance are the leading causes of therapeutic failures. The Chen Lab (https://www.stjude.org/research/labs/chen-lab-taosheng.html) studies: (1) the chemical regulation of nuclear xenobiotic receptors, (2) the mechanism of selective modulation of highly homologous drug-metabolizing enzymes. We are taking a hypothesis-driven and technology-enabled multidisciplinary approach to develop chemical probes, investigate biological mechanisms, and evaluate in vivo efficacy. In particular we use the promiscuous pregnane X receptor (PXR) and constitutive androstane receptor (CAR) as models. PXR and CAR transcriptionally regulate cytochrome P450 3A4 (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; Nat Commun 15:4054, 2024); established that PXR and CAR form an unexpected heterodimer (Nucleic Acids Res 50:3254, 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 to understand nuclear receptor-regulated transcription networks, enzyme-drug interactions, and design therapeutic approaches to overcome drug resistance and toxicity in cellular and animal models.

The postdoctoral fellows will work in a multidisciplinary team to study the regulation of PXR and CAR, or CYP3A4 and CYP3A5, by characterizing novel chemical probes (i.e., small molecule inhibitors or degraders) in biochemical/biophysical, cellular and animal models. The fellows will contribute to or lead the effort of the multidisciplinary team (of biologists, medicinal chemists and structural biologists), organize and prepare manuscripts for publications. The fellows will be trained on manuscript and grant writing and encouraged (but not required) to prepare and submit grant proposals.

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