Discovery of a novel inhibitor of constitutive androstane receptor (CAR) that does not activate pregnane X receptor (PXR) (SJ-14-0039)

St. Jude Reference #SJ-14-0039


Researchers at St. Jude used a directed screening approach and identified a novel, potent, specific, and non-toxic CAR inhibitor (CINPA1) with an IC50 of ~70nM in cell-based assays, among around 1000 candidates known not to activate PXR.

Constitutive androstane receptor (CAR, NR1I3) and pregnane X receptor (PXR, NR1I2) are master regulators of endobiotic and xenobiotic metabolism and disposition. Because CAR is constitutively active in certain cellular contexts, inhibiting CAR might reduce drug-induced hepatotoxicity and resensitize drug resistant cancer cells to chemotherapeutic drugs. Researchers at St. Jude discovered a novel CAR inhibitor/inverse agonist, CINPA1, and obtained or designed 54 analogs of CINPA1 and used a time-resolved fluorescence resonance energy transfer (TR-FRET) assay to evaluate their CAR inhibition potency. Many of the 54 analogs showed CAR inverse agonistic activities higher than those of CINPA1. Among them, number 72, is about 59-fold more potent than CINPA1 and over 10-fold more potent than clotrimazole, the most potent CAR inverse agonist in a biochemical assay previously reported by others. Docking studies provide a molecular explanation of the structure activity relationship (SAR) observed experimentally. To our knowledge, this effort is the first chemistry endeavor in designing and identifying potent CAR inverse agonists based on a novel chemical scaffold, leading to 72 as the most potent CAR inverse agonist so far. The 54 chemicals presented are novel and unique tools for characterizing CAR's function, and the SAR information gained from these 54 analogs could guide future efforts to develop improved CAR inverse agonists.

CINPA1 can be used to counteract the activity of CAR, and will be a novel research tool to study CAR function. Potential commercial applications include using CINPA1 as a “co-drug” with existing chemotherapeutics, to attenuate CAR-mediated drug-drug interactions, toxicity, and drug resistance, and improve therapeutic efficacy and safety. CINPA1 had not been publically disclosed prior to the related publication; however, it is available commercially now.


Constitutive androstane receptor, CINPA1, Inverse agonist, TR-FRET

Granted patents or published applications

Issued US Patent 9,908,890

Related scientific references

Chen, et al., Development of CINPA1 analogs as novel and potent inverse agonists of constitutive androstane receptor, European Journal of Medicinal Chemistry 108 (2016) 505-528

Cherian MT, Lin W, Wu J, Chen T. CINPA1 is an inhibitor of constitutive androstane receptor (CAR) that does not activate pregnane X receptor (PXR). Mol Pharmacol 87(5): 878-889, 2015.

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