8WUY

Crystal Structure of TR3 LBD in complex with para-positioned 3,4,5-trisubstituted benzene derivatives

Summary for 8WUY

• Entry DOI: 10.2210/pdb8wuy/pdb
• Descriptor: Nuclear receptor subfamily 4immunitygroup A member 1, ~{N}-methyl-~{N}-octyl-3,4,5-tris(oxidanyl)benzamide (3 entities in total)
• Functional Keywords: complex, transcription
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 2
• Total formula weight: 55381.30

Authors

Hong, W.B.,Chen, X.Q.,Lin, T.W. (deposition date: 2023-10-21, release date: 2024-01-24, Last modification date: 2024-01-31)

Primary citation

Hong, W.,Xiao, T.,Lin, G.,Liu, C.,Li, H.,Li, Y.,Hu, H.,Wu, S.,Wang, S.,Liang, Z.,Lin, T.,Liu, J.,Chen, X.
Structure-based design and synthesis of anti-fibrotic compounds derived from para-positioned 3,4,5-trisubstituted benzene.
Bioorg.Chem., 144:107113-107113, 2024

PubMed Abstract: Liver fibrosis is an abnormal wound-healing response to liver injuries. It can lead to liver cirrhosis, and even liver cancer and liver failure. There is a lack of treatment for liver fibrosis and it is of great importance to develop anti-fibrotic drugs. A pivotal event in the process of developing liver fibrosis is the activation of hepatic stellate cells (HSCs), in which the nuclear receptor Nur77 plays a crucial role. This study aimed to develop novel anti-fibrotic agents with Nur77 as the drug target by modifying the structure of THPN, a Nur77-binding and anti-melanoma compound. Specifically, a series of para-positioned 3,4,5-trisubstituted benzene ring compounds with long-chain backbone were generated and tested for anti-fibrotic activity. Among these compounds, compound A8 was with the most potent and Nur77-dependent inhibitory activity against TGF-β1-induced activation of HSCs. In a crystal structure analysis, compound A8 bound Nur77 in a peg-in-hole mode as THPN did but adopted a different conformation that could interfere the Nur77 interaction with AKT, which was previous shown to be important for an anti-fibrotic activity. In a cell-based assay, compound A8 indeed impeded the interaction between Nur77 and AKT leading to the stabilization of Nur77 without the activation of AKT. In a mouse model, compound A8 effectively suppressed the activation of AKT signaling pathway and up-regulated the cellular level of Nur77 to attenuate the HSCs activation and ameliorate liver fibrosis with no significant toxic side effects. Collectively, this work demonstrated that Nur77-targeting compound A8 is a promising anti-fibrotic drug candidate.

PubMed: 38232685
DOI: 10.1016/j.bioorg.2024.107113

Experimental method

X-RAY DIFFRACTION (2.6 Å)