Project Description: 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. Position Responsibilities: 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. Minimum Education and/or Training: Individuals with a strong publication record in reputable journals and are motivated to perform high quality research and publish impactful papers are encouraged to apply. Candidates must have (or soon receive) a PhD degree in biology, chemical biology, or structural biology. Special Skills, Knowledge, and Abilities: Required skills: For a PhD in Biology/Chemical Biology/Pharmacology: cell & molecular biology, chemical biology, or in vivo pharmacology (mouse models) For a PhD in Structural Biology: protein expression and purification, X-ray crystallography, in silico modeling of protein-ligand interactions Preferred skills: experience in using multidisciplinary chemical biology approaches to investigate protein-ligand interactions and understand the mechanistic insights and in vitro/in vivo functional outcomes. Soft skills: effective communications skills; ability to work independently and collaboratively; willing to and capable of learning new skills needed to complete the research projects. About the lab and St. Jude: Upon completion of the training, the trainees are expected to become independent researchers or leaders in either academic or industrial settings. The Chen Lab provides a unique training environment: in addition to basic mechanistic chemical 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; collaborate with senior staff members from diverse background (biologists, structural biologists and medicinal chemists). Former Chen Lab postdocs have landed jobs as Assistant Professors in Universities, Senior Scientists in Pharmaceutical Companies, or Staff Scientists at St. Jude. St. Jude Children’s Research Hospital is a world-class research institution dedicated to pediatric cancer and other catastrophic diseases of childhood. The first and only National Cancer Institute (NCI)-designated Comprehensive Cancer Center devoted solely to children. Our 300 faculty work across the spectrum of basic, translational, clinical, and population science in a highly collaborative multidisciplinary environment that includes a Nobel laureate and members of the National Academy of Science and the National Academy of Medicine. St. Jude is ranked on Fortune Magazine’s “Best Workplaces in Health Care & Biopharma” and Glassdoor’s “Best Places to Work,” and is located in the heart of Memphis, Tennessee, a vibrant and friendly city at the historic American crossroads of music, trade, food and culture. We are in pursuit of the brightest minds in biomedical sciences, individuals poised to contribute to our research progress. Other than access to top-quality scientists and mentors, as a postdoctoral trainee at St. Jude, you will have: A Blend of Academic Freedom and Industrial Efficiency: Access to shared resources and facilities led by expert scientists, coupled with cutting-edge technology, accelerates research productivity. Customized Professional and Career Growth: Experience specifically designed programs to enhance professional growth and career readiness empowering postdocs for success beyond their training. This includes access to grant writing workshops, individual development plans, teaching and mentoring opportunities, non-research career advancement programs, professional development allowance, and so much more. Competitive Compensation: Embark on your journey with a competitive salary starting at > $70,000 a year, comprehensive benefits and generous relocation assistance, reflecting our commitment to recognize and invest in talent. A Sense of Community: St. Jude fosters a vibrant postdoc community that supports a well-balanced life. A dynamic environment promotes connections and camaraderie among postdocs from all backgrounds. Diversity, Equity and Inclusion St. Jude Children’s Research Hospital has a diverse, global patient population and workforce, built on the principles of diversity, equity and inclusion. Our founder Danny Thomas envisioned a hospital that would treat children of the world—regardless of race, religion or a family’s ability to pay. Learn more about our history and commitment. Today, we continue the mission to advance cures and means of prevention for pediatric catastrophic diseases through research and treatment. As we accelerate this progress globally, we believe our legacy of diversity, equity and inclusion is foundational to success. With the commitment of leaders at all levels of the organization, we strive to ensure the St. Jude culture, leadership approaches and talent processes are equitable and culturally responsive. View our Diversity, Equity and Inclusion Report to learn about the hospital’s roots in diversity, equity and inclusion, where we are today and our aspirations for an even better future. St. Jude is an Equal Opportunity Employer No Search Firms St. Jude Children's Research Hospital does not accept unsolicited assistance from search firms for employment opportunities. Please do not call or email. All resumes submitted by search firms to any employee or other representative at St. Jude via email, the internet or in any form and/or method without a valid written search agreement in place and approved by HR will result in no fee being paid in the event the candidate is hired by St. Jude.