FXR modulators for enterohepatic and metabolic diseases

ABSTRACT

Introduction: Farnesoid X receptor (FXR), a nuclear receptor mainly expressed in enterohepatic tissues, is a master for bile acid, lipid and glucose homeostasis. Additionally, it acts as a cell protector with unclear mechanism but may be implicated in combating against inflammation, fibrosis and cancers. FXR is thus accepted as a promising target particularly for the enterohepatic diseases, and numerous FXR modulators have been patented and developed.

Areas covered: This review provides an update on the development of FXR modulators for enterohepatic diseases and offers an in-depth perspective on new strategies for the development of novel FXR modulators.

Expert opinion: Despite the development of numerous FXR modulators, which culminated in the successful launch of obeticholic acid (OCA), it remains a matter of debate on how the function of FXR should be exploited for therapeutic purposes. The improvement for obesity achieved by either FXR agonists or antagonists is still in confusion. Whether the side effect of pruritus induced by OCA could be exempted for non-steroidal FXR agonists needs further validation. Apart from the development of conventional FXR ligands, emerging evidence support that restoration of FXR protein level may represent a new strategy in targeting FXR for enterohepatic and metabolic diseases.

KEYWORDS:

• Farnesoid X receptor
• enterohepatic diseases
• metabolic diseases
• agonists
• antagonists

Article highlights

• Due to its paramount importance in maintaining BAs/glucose/lipid homeostasis, as well as in the regulation of inflammation/fibrosis, FXR plays a pivotal role in the pathogenesis of a wide range of enterohepatic diseases, including cholestatic liver diseases, obesity, NASH, liver fibrosis, and cancer.

• Numerous FXR modulators including agonists and antagonists with diverse chemical structures have been developed, and obeticholic acid (OCA) has been licenced by FDA and EMEA for the therapy of primary biliary cholangitis (PBC). Moreover, several other patented FXR modulators are on clinical trials for enterohepatic and metabolic diseases.

• In addition to the development of new FXR ligands with minimized side effects, emerging evidence support that the restoration of FXR protein levels may represent a new strategy for better targeting FXR.

• Several strategies for the development of FXR modulators, including tissue-specific and target gene-selective modulators, modulators to regulate the PTMs of FXR, as well as combinatorial use with other therapeutic agents, have been proposed.

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Declaration of interest

The authors have no relevant affiliations for financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or opinions, expert testimony, grants or patents received or pending or royalties.

Reviewer disclosures

A peer review on this manuscript declares that they are a cofound of TES Pharma. All other peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This research was supported by National Natural Science Foundation of China [grants 81430091, 81720108032, 81421005, 91429308, 81530098, 81603194 and 21602254]; the Project for Major New Drug Innovation and Development [grant 2015ZX09501010]; and Overseas Expertise Introduction Project for Discipline Innovation [G20582017001]; and China Postdoctoral Science Foundation [grants 2016M600455 and 2017T100423].