A Novel FXR-Targeted DUBTAC and Its Applications in Cholestasis Therapy

Farnesoid X receptor (FXR) is critical for cholestatic
liver disease
therapy, but FXR agonists often show compromised efficacy due to FXR
protein degradation under pathological conditions. Here, we report
the first discovery of potent FXR DUBTAC stabilizer D11 as a candidate for cholestasis. We designed and synthesized
31 novel compounds by tethering canonical FXR ligands (e.g., OCA,
CDCA) to the OTUB1 ligand EN523 via diverse linkers. D11 elevated FXR protein levels in HepG2 cells in a dose- and
time-dependent manner, and its action required a functional ubiquitin-proteasome
system. It also significantly increased the hepatic FXR protein level
in mice with α-naphthylisothiocyanate (ANIT)-induced cholestasis
liver injury. Importantly, D11 demonstrated
excellent hepatoprotective efficacy against cholestasis with a reliable
safety profile. Thus, D11 emerges as a promising
lead compound for FXR-targeted cholestasis therapy, paving a new avenue
for drug development by stabilizing, rather than merely activating
the receptor.