Table 1.

Summarized for pregnane X receptor (PXR) or constitutive androstane receptor (CAR): critical target genes or protein-protein interaction partners, clinical implications, small molecule targeting approach, assay design, assay development and possible challenges associated with the drug discovery process

PXR or CAR	Target gene or protein– protein interaction partner of PXR or CAR	Clinical implications	Targeting approach	Assay design and development	Significance	Challenges
PXR	Cytorchrome P450 (CYP)3A4	Drug metabolism Drug–drug interactions (DDIs)	PXR agonists to enhance drug metabolism PXR antagonists to decrease drug metabolism and associated DDIs	Small molecule HTS using biochemical time-resolved fluorescence resonance energy transfer (TR-FRET) assays [93] and cell-based luciferase reporter assays [71,92] Virtual screening of small molecules using PXR crystal structures [78,89]	Potent and/or selective PXR modulators to regulate CYP3A4 levels	Finding potent and selective compounds Lack of X-ray crystal structure for PXR bound to antagonist
PXR	p53	Compromised drug efficacy in cancer cells with mutated p53	Small molecules that restore the inhibitory effect of mutated p53 on PXR	Cell-based reporter assays in the presence of either wild-type or mutated p53 Biochemical assays to investigate the binding of compound to PXR or p53	Small molecules that restore the inhibitory effect of mutated p53 on PXR might enhance drug efficacy and reduce drug resistance	No specific site known for PXR–p53 interaction No crystal structure or mechanism available on how p53 binds to PXR
PXR	Nuclear factor (NF)-κB	Inflammatory diseases	PXR agonists	Cell-based luciferase reporter assays to identify compounds that inhibit NF-κB activity in a PXR- dependent manner [37]	Potent and/or selective PXR agonists to inhibit NF-κB with possible therapeutic implications in treating diseases such as inflammatory bowel disorder (IBD)	Identifying specific PXR activators that are also NF-κB inhibitors
PXR	Fibroblast growth factor (FGF)19	Tumor aggressiveness	PXR antagonists	Cell-based luciferase reporter assay to identify PXR antagonists that reduce the levels of FGF19 in a HTS format [46]	Potent and selective PXR antagonists to inhibit FGF19 expression with potential anticancer properties	Identifying selective antagonists to regulate FGF19 in a tumor-specific manner
CAR	CYP2B6	Drug metabolism DDIs	CAR agonists to enhance drug metabolism CAR antagonists or inverse agonists to decrease drug metabolism and associated DDIs	HTS using cell-based luciferase reporter assays [40] Virtual screening of small molecules using CAR crystal structures [94]	Potent selective CAR modulators to regulate CYP2B6	Finding potent and selective compounds Lack of crystal structure for CAR bound to antagonist or inverse agonist
CAR	Growth arrest and DNA-damage- inducible beta (GADD45B)	Resistance to apoptosis mediated by CAR-GADD45B interaction	CAR inverse agonist that disrupts GADD45B binding [54]	*Fluorescence polarization assay using GADD45B peptide.	Disruption of CAR- GADD45B interaction can increase chemsensitivity to anticancer drugs	No specific site known for CAR –GADD45B interaction