9LQ3

Crystal structure of Linafexor-FXR complex

This is a non-PDB format compatible entry.

Summary for 9LQ3

• Entry DOI: 10.2210/pdb9lq3/pdb
• Descriptor: Bile acid receptor, Nuclear receptor coactivator 2, Linafexor, ... (4 entities in total)
• Functional Keywords: bile acid receptor, nonbile acid agonist, linafexor, nuclear protein
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 2
• Total formula weight: 28429.56

Authors

Yao, B.,Li, Y. (deposition date: 2025-01-27, release date: 2025-08-06, Last modification date: 2026-06-24)

Primary citation

Zang, Y.,Shi, J.,Zhao, G.,Tang, B.,Liu, M.,Yao, B.,Wang, G.,Pan, H.,Yang, S.,Deng, R.,Zhao, Y.,Zhang, Z.,Guo, H.R.,Sun, D.D.,Wang, H.,Gao, L.,Yu, J.,Diao, X.,Li, Y.,Li, J.,Xu, H.E.
A first-in-class pulsatile FXR agonist for bile-acid-related liver diseases.
Nature, 2026

PubMed Abstract: Nuclear receptors are central regulators of metabolism, yet therapeutic strategies that enforce continuous receptor activation frequently lead to reduced efficacy and unacceptable toxicity. Here we report a first-principles drug design strategy that aligns pharmacokinetics with physiological signalling cycles. We developed linafexor, a potent non-bile-acid agonist of the farnesoid X receptor (FXR); it is engineered for rapid systemic clearance, which enables pulsatile receptor activation that mirrors endogenous bile acid dynamics. Linafexor has robust efficacy across multiple preclinical models of metabolic dysfunction-associated steatohepatitis, liver fibrosis, primary biliary cholangitis and primary sclerosing cholangitis. Transcriptomic analyses reveal that, unlike long-acting FXR agonists, linafexor preserves cyclic FXR signalling, avoids receptor downregulation and prevents broad transcriptional dysregulation. Direct manipulation of delivery patterns demonstrates that sustained FXR activation-independent of compound identity-induces severe toxicity, establishing activation duration as a determinant of therapeutic index. In phase 1 clinical studies (ClinicalTrials.gov; NCT05082779), linafexor administered once daily produces transient FXR pathway engagement, marked by (1) induction of FGF19, a key endocrine mediator of bile acid feedback regulation; and (2) suppression of C4, an intermediate reflecting hepatic bile acid synthesis, with no treatment-related adverse events. Together, these findings identify pulsatile FXR activation as a mechanistically grounded and clinically translatable strategy, and establish linafexor as a first-in-class therapeutic for bile acid-related liver diseases.

PubMed: 42271063
DOI: 10.1038/s41586-026-10633-1

Experimental method

X-RAY DIFFRACTION (2.8 Å)