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Discovery of novel liver X receptor inverse agonists as lipogenesis inhibitors.

Abstract：

:Based on the co-crystal structures of LXRβ and its agonists (spiro [pyrrolidine-3,3'-oxindole] derivatives) discovered by us previously, we designed and synthesized a compound library to explore the agonistic activities. The library was screened with luciferase reporter assays, interestingly, it resulted in the discovery of 10 LXR inverse agonists besides 5 LXR agonists. To clarify the mechanism of the actions, we conducted molecular dynamics (MD) simulations on the LXR and inverse agonists complexes, and revealed that H3, H11 and H12 configurations are the key to turn on agonism or inverse agonism status for LXR. Binding tightly with H3, pushing H11 out and destabilizing H12 could form a bigger hydrophobic groove to accommodate NCOR1 to turn on LXR inverse agonism. The inverse agonist 10rr was further studied, and found as a lipogenesis inhibitor through down-regulating LXR target genes SREBP-1c, ACC, FAS and SCD-1, and demonstrated lipid-lowering effects in 3T3-L1 cells, HepG2 cells and mice with Triton WR-1339-induced hyperlipidemia. Therefore, we have proved that LXR inverse agonists can be promising agents for hyperlipidemia treatment.

journal_name

Eur J Med Chem

journal_title

European journal of medicinal chemistry

authors

Chen Z,Chen H,Zhang Z,Ding P,Yan X,Li Y,Zhang S,Gu Q,Zhou H,Xu J

doi

10.1016/j.ejmech.2020.112793

subject

Has Abstract

pub_date

2020-11-15 00:00:00

pages

112793

eissn

0223-5234

issn

1768-3254

pii

S0223-5234(20)30765-0

journal_volume

206

pub_type

杂志文章

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