Pregnane X Receptor (PXR) Degrader

MI1013 is a PROTAC PXR degrader (DC₅₀ = 89 nM, D_max = 82%). MI1013 degrades PXR in human hepatocellular carcinoma RG cells (HepaRG). MI1013 specifically and safely regulates CYP3A4 promoter activity through PXR degradation. MI1013 affects several key genes involved in sulfate conjugation (e.g., SULT1E1), bile acid synthesis (CYP7A1), gluconeogenesis (PCK1), ketone synthesis (HMGCS20), and hepatocyte proliferation (MKI67). (Pink: PXR ligand 3: HY-175267, Blue: Pomalidomide-propargyl ligand: HY-W410002, Pink + Black: PXR ligand-Linker Conjugate 1: HY-175268).

SJYHJ-026 is a PROTAC degrader targeting PXR, with a DC₅₀ of 86.6 nM in SNU-C4 HiBiT-PXR KI cells. SJYHJ-026 shows higher selectivity for PXR over CAR, VDR, FXR, LXRα and LXRβ, and can bind to VHL to form a PXR-SJYHJ-026-VHL complex, inducing proteasomal degradation of PXR. SJYHJ-026 blocks agonist-induced PXR-mediated gene expression (including CYP3A4) and reduces basal PXR activity at the CYP3A4 promoter. SJYHJ-026 can be used for the research of colorectal cancer.

PROTAC PXR degrader-1 is a PROTAC degrader targeting PXR, with a DC₅₀ value of 49.8 nM in SNU-C4 3xFLAG-PXR KI cells. PROTAC PXR degrader-1 exhibits selectivity towards CAR, VDR, FXR, LXRα and LXRβ. PROTAC PXR degrader-1 induces the formation of a ternary complex with PXR and VHL, triggering proteasomal degradation of PXR. PROTAC PXR degrader-1 reduces both agonist-induced and basal PXR-mediated CYP3A4 promoter activation, and decreases the expression of endogenous CYP3A4 gene in cancer cells. PROTAC PXR degrader-1 enhances the cytotoxic effect of paclitaxel on cancer cells. PROTAC PXR degrader-1 can be used for the research of colorectal cancer.