From functional complexity to structural modification: A systematic review of the ongoing development of targeted PXR drugs.

The pregnane X receptor (PXR, NR1I2) is a ligand-activated nuclear receptor that regulates xenobiotic and endobiotic metabolism and has been associated with diverse physiological and pathological processes. However, the biological consequences of PXR modulation are highly context-dependent, and the translational relevance of many reported effects remains incompletely defined. The remarkable structural plasticity of the PXR ligand-binding pocket (LBP), together with its context-dependent effects in disease progression, poses substantial challenges for the development to potent and highly selective modulators. Intrinsic limitations of current PXR-targeted agents, including suboptimal target selectivity, significant off-target effects, adverse outcomes from systemic activation, and an incomplete understanding of PXR-mediated physiological mechanisms, have limited the clinical translation of most agonists and antagonists to the preclinical stage. In this review, we provide a concise overview of the structural feature and physiological functions of PXR. We summarize its multifaceted associations with human diseases and examine the structure-activity relationships (SAR), design strategies, and molecular mechanisms of small-molecule PXR modulators from a medicinal chemistry perspective. We also highlight actionable strategies that integrate emerging technologies and innovative approaches to improve target selectivity and achieve more precise transcriptional modulation. Collectively, these insights provide a framework for the rational optimization and evaluation of PXR-targeted modulators.