A new mode of inhibition.

Complementary structural biology approaches reveal how an agonist and a covalent inhibitor simultaneously bind to a nuclear receptor.

Chemical manipulation of an activation/inhibition switch in the nuclear receptor PXR.

Nuclear receptors are ligand-activated transcription factors that can often be useful drug targets. Unfortunately, ligand promiscuity leads to two-thirds of receptors remaining clinically untargeted. PXR is a nuclear receptor that can be activated by diverse compounds to elevate metabolism, negatively impacting drug efficacy and safety. This presents a barrier to drug development because compounds designed to target other proteins must avoid PXR activation while retaining potency for the desired target. This problem could be avoided by using PXR antagonists, but these compounds are rare, and their molecular mechanisms remain unknown. Here, we report structurally related PXR-selective agonists and antagonists and their corresponding co-crystal structures to describe mechanisms of antagonism and selectivity. Structural and computational approaches show that antagonists induce PXR conformational changes incompatible with transcriptional coactivator recruitment. These results guide the design of compounds with predictable agonist/antagonist activities and bolster efforts to generate antagonists to prevent PXR activation interfering with other drugs.

CYP3A5 unexpectedly regulates glucose metabolism through the AKT-TXNIP-GLUT1 axis in pancreatic cancer.

CYP3A5 is a cytochrome P450 (CYP) enzyme that metabolizes drugs and contributes to drug resistance in cancer. However, it remains unclear whether CYP3A5 directly influences cancer progression. In this report, we demonstrate that CYP3A5 regulates glucose metabolism in pancreatic ductal adenocarcinoma. Multi-omics analysis showed that CYP3A5 knockdown results in a decrease in various glucose-related metabolites through its effect on glucose transport. A mechanistic study revealed that CYP3A5 enriches the glucose transporter GLUT1 at the plasma membrane by restricting the translation of TXNIP, a negative regulator of GLUT1. Notably, CYP3A5-generated reactive oxygen species were proved to be responsible for attenuating the AKT-4EBP1-TXNIP signaling pathway. CYP3A5 contributes to cell migration by maintaining high glucose uptake in pancreatic cancer. Taken together, our results, for the first time, reveal a role of CYP3A5 in glucose metabolism in pancreatic ductal adenocarcinoma and identify a novel mechanism that is a potential therapeutic target.

Regulation of PXR in drug metabolism: chemical and structural perspectives.

INTRODUCTION: Pregnane X receptor (PXR) is a master xenobiotic sensor that transcriptionally controls drug metabolism and disposition pathways. PXR activation by pharmaceutical drugs, natural products, environmental toxins, etc. may decrease drug efficacy and increase drug-drug interactions and drug toxicity, indicating a therapeutic value for PXR antagonists. However, PXR's functions in physiological events, such as intestinal inflammation, indicate that PXR activators may be useful in certain disease contexts. AREAS COVERED: We review the reported roles of PXR in various physiological and pathological processes including drug metabolism, cancer, inflammation, energy metabolism, and endobiotic homeostasis. We then highlight specific cellular and chemical routes that modulate PXR activity and discuss the functional consequences. Databases searched and inclusive dates: PubMed, 1 January 1980 to 10 January 2024. EXPERT OPINION: Knowledge of PXR's drug metabolism function has helped drug developers produce small molecules without PXR-mediated metabolic liabilities, and further understanding of PXR's cellular functions may offer drug development opportunities in multiple disease settings.