Discovery of new LXRß agonists as glioblastoma inhibitors.
Eur J Med Chem
; 194: 112240, 2020 May 15.
Article
em En
| MEDLINE
| ID: mdl-32248003
ABSTRACT
Discovery and optimization of selective liver X receptor ß (LXRß) agonists are challenging due to the high homology of LXRα and LXRß 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, LXRß selective agonists were designed and synthesized. This led to the discovery of LXRß 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.
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MEDLINE
Assunto principal:
Pirrolidinas
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Compostos de Espiro
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Glioblastoma
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Descoberta de Drogas
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Receptores X do Fígado
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Oxindóis
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Antineoplásicos
Idioma:
En
Ano de publicação:
2020
Tipo de documento:
Article