Postdoctoral Research Associate - Chemical Biology & Therapuetics

The Chen Lab studies how chemical and structural mechanisms govern xenobiotic sensing, drug metabolism, and therapeutic response. Our research integrates structure-based drug design, chemical biology, medicinal chemistry, structural biology, and molecular and cellular biology to develop chemical tools and therapeutic strategies for understanding and overcoming drug toxicity and resistance.

A major focus of the lab is the chemical regulation of PXR and CAR, which transcriptionally regulate CYP3A enzymes responsible for the metabolism of more than half of clinically used drugs. We also investigate the molecular basis for selective modulation of the highly homologous drug-metabolizing enzymes CYP3A4 and CYP3A5. These systems provide challenging and biologically important models for understanding how dynamic protein structures, ligand recognition, transcriptional regulation, and enzyme-drug interactions influence therapeutic response.

Our work has established several new concepts and chemical approaches in these areas. We developed the first selective PXR antagonists (Nature Communications 8:741, 2017; Nature Communications 15:4054, 2024) and PXR degraders (Journal of Medicinal Chemistry 67:18549, 2024; Nature Communications 16:9805, 2025); revealed an unexpected PXR-CAR heterodimer and its functional implications (Nucleic Acids Research 50:3254, 2022); uncovered a mechanism by which PXR dynamically expands its ligand-binding pocket to modulate ligand affinity (PNAS 120:e2217804120, 2023); and discovered CYP3A5-selective and CYP3A4-selective inhibitors, together with the structural basis for their selectivity (JACS 143:18467, 2021; Nature Communications 16:3423, 2025).

The successful candidate will lead cell and molecular biology efforts at the interface of chemical biology and structural biology, with responsibilities to:

• Lead the biological characterization of novel ligands, inhibitors, and targeted protein degraders developed in the lab, and establish their mechanisms of action.
• Develop and implement hypothesis-driven cellular and molecular approaches to investigate PXR and CAR regulation, transcriptional networks, or the selective modulation of CYP3A4 and CYP3A5.
• Collaborate closely with in-house structural biologists, chemists, and SBDD scientists to connect molecular structure with biological activity and mechanism, and to iteratively guide compound optimization.
• Evaluate promising chemical probes and therapeutic strategies in cellular and in vivo models to investigate drug metabolism, toxicity, and resistance.
• Lead multidisciplinary manuscripts and contribute to the development of new research directions arising from mechanistic and chemical biology studies.

A distinctive feature of these projects is the opportunity to study proteins with large, flexible, and highly dynamic ligand-binding pockets and promiscuous ligand-binding profiles, creating both significant challenges and opportunities for innovative multidisciplinary research. The lab combines hypothesis-driven mechanistic research with technology-enabled approaches, enabling molecular-level discoveries to be translated into new chemical tools and potential therapeutic strategies.

This position is particularly well suited for a scientist with demonstrated expertise in cell and molecular biology who is capable of independently developing and leading biological strategies to investigate PXR and CAR regulation and their transcriptional networks, or the selective modulation of CYP3A4 and CYP3A5. The candidate should also have a working understanding of structural biology, medicinal chemistry, and chemical biology to foster meaningful collaborations and use structural and chemical information to formulate and test biological hypotheses. Experience or strong interest in chemical biology, nuclear receptor biology, drug metabolism, or protein degradation will be valuable.

The successful candidate should be excited by mechanism-driven, multidisciplinary research at the interface of molecular biology, chemical biology, structural biology, and therapeutic development, and motivated to take scientific ownership of projects from biological hypothesis through mechanistic discovery and translational validation.

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