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.
Cui et al. (Fri,) studied this question.