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Discovery of new LXRβ agonists as glioblastoma inhibitors
Hao Chen1, Ziyang Chen1, Zizhen Zhang1
1Guangdong Provincial Key Laboratory of New Drug Design and Evaluation, Research Center for Drug Discovery at School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou, 510006, China.
Abstract:
Discovery and optimization of selective liver X receptor β (LXRβ) agonists are challenging due to the high homology of LXRα and LXRβ in the ligand-binding domain. There is only one different residue (Val versus Ile) at the ligand-binding pocket of LXRs. With machine learning methods, we identified pan LXR agonists with a novel scaffold (spiro[pyrrolidine-3,3'-oxindole]). Then, we figured out the mechanism of LXR isoform selectivity from co-crystal structures. Based on the mechanism and the new scaffold, LXRβ selective agonists were designed and synthesized. This led to the discovery of LXRβ agonists 4-7rr, 4-13 and 4-13rr with IC50 values ranging from 1.78 to 6.36 μM against glioblastoma in vitro. Treatment with 50 mg/kg/day of 4-13 for 15 days significantly reduced tumor growth using an in vivo xenograft glioblastoma model.
Insights
Researchers developed novel liver X receptor beta (LXRβ) agonists using machine learning. These compounds show promise in treating glioblastoma, significantly reducing tumor growth in preclinical models.
Area of Science:
- Medicinal Chemistry
- Molecular Pharmacology
- Computational Chemistry
Background:
- Selective targeting of liver X receptor beta (LXRβ) is difficult due to high homology with LXRα.
- A single amino acid difference in the ligand-binding domain complicates isoform-selective drug design.
Purpose of the Study:
- To identify novel agonists targeting LXR isoforms.
- To design and synthesize selective LXRβ agonists for glioblastoma treatment.
- To elucidate the mechanism of LXR isoform selectivity.
Main Methods:
- Machine learning identified initial pan LXR agonists with a spiro[pyrrolidine-3,3'-oxindole] scaffold.
- Co-crystal structures were used to understand LXR isoform selectivity mechanisms.
- Structure-based design and synthesis yielded selective LXRβ agonists.
Main Results:
- Novel LXRβ agonists (4-7rr, 4-13, 4-13rr) were discovered with IC50 values from 1.78 to 6.36 μM against glioblastoma in vitro.
- Compound 4-13 demonstrated significant glioblastoma tumor growth reduction in an in vivo xenograft model at 50 mg/kg/day.
- The study elucidated the structural basis for LXR isoform selectivity.
Conclusions:
- The developed LXRβ agonists represent a promising new therapeutic strategy for glioblastoma.
- The combination of machine learning and structural biology enabled the discovery of selective LXRβ agonists.
- Preclinical data support the potential of LXRβ agonists in glioblastoma treatment.
