Allosteric Antagonism of the Pregnane X Receptor (PXR): Current-State-of-the-Art and Prediction of Novel Allosteric Sites

Abstract

The pregnane X receptor (PXR, NR1I2) is a xenobiotic-activated transcription factor with high levels of expression in the liver. It not only plays a key role in drug metabolism and elimination, but also promotes tumor growth, drug resistance, and metabolic diseases. It has been proposed as a therapeutic target for type II diabetes, metabolic syndrome, and inflammatory bowel disease, and PXR antagonists have recently been considered as a therapy for colon cancer. There are currently no PXR antagonists that can be used in a clinical setting. Nevertheless, due to the large and complex ligand-binding pocket (LBP) of the PXR, it is challenging to discover PXR antagonists at the orthosteric site. Alternative ligand binding sites of the PXR have also been proposed and are currently being studied. Recently, the AF-2 allosteric binding site of the PXR has been identified, with several compounds modulating the site discovered. Herein, we aimed to summarize our current knowledge of allosteric modulation of the PXR as well as our attempt to unlock novel allosteric sites. We describe the novel binding function 3 (BF-3) site of PXR, which is also common for other nuclear receptors. In addition, we also mention a novel allosteric site III based on in silico prediction. The identified allosteric sites of the PXR provide new insights into the development of safe and efficient allosteric modulators of the PXR receptor. We therefore propose that novel PXR allosteric sites might be promising targets for treating chronic metabolic diseases and some cancers.

Targeted Protein Degradation (TPD) for Immunotherapy: Understanding Proteolysis Targeting Chimera-Driven Ubiquitin-Proteasome Interactions

“…PROTAC offers a novel strategy to design small-molecule immunotherapeutic that can overcome the limitations of macromolecular drugs, such as poor oral bioavailability, tissue penetration, and transmembrane transport. PROTAC can benefit from the development of new E3 ligases, linkers, and delivery systems, as well as the integration of novel technologies, such as photochemical control, molecular glues, allosteric 209 and in-cell click chemistry, 210 to improve the efficiency and selectivity of protein degradation. Although the development of PROTAC-based immunotherapy is still in its early stages, it has the potential to revolutionize cancer treatment.…”

A potent agonist-based PROTAC targeting Pregnane X Receptor that delays colon cancer relapse

“…However their efficacy (Poulton et al , 2013) and safety make them unsuitable for clinical use (Fuchs et al , 2013). Thus, despite the considerable interest in targeting PXR in cancers or in preventing and overcoming drug-induced PXR-mediated drug toxicity and drug resistance, there is currently no PXR antagonist for clinical trials (Kamaraj et al , 2022).…”