MI1013 is a PROTAC PXR degrader with a DC50 of 89 nM and a Dmax of 82%. It degrades PXR in human liver cancer RG cells (HepaRG) and modulates CYP3A4 promoter activity with specificity and safety through PXR degradation. MI1013 influences key genes involved in sulfate conjugation (e.g., SULT1E1), bile acid synthesis (CYP7A1), gluconeogenesis (PCK1), ketogenesis (HMGCS20), and hepatocyte proliferation (MKI67).

MI1013, at concentrations of 0.01 to 10 μM over 0-96 hours, induces PXR degradation in HepaRG and MOLT4 cells without affecting RXRα and GSPT1 degradation. At concentrations of 1-10 μM for 24 hours, MI1013 can inhibit PXR and PXR-HiBiT degradation in HepaRG cells using a CYP3A4 gene promoter luciferase construct, yet it does not exhibit agonist activity even at concentrations up to 10 μM. It exhibits low binding competitiveness with the PXR LBD. MI1013, administered for 24 hours up to 100 μM, is non-toxic in HepaRG, HK-2, COS-1, and HepG2 cells. At 2 μM for 24 hours, MI1013 effectively modulates PXR activity, restoring CAR function in HepaRG cells. Additionally, MI1013 at the same concentration and duration downregulates mRNA levels of CYP3A4, SULT1E1, SULT1B1, CYP7B1, NR0B2, and CYP7A1 while upregulating UGT1A1 mRNA levels in both HepaRG and human liver cells.