Discovery of new LXRβ agonists as glioblastoma inhibitors

Eur J Med Chem. 2020 May 15;194:112240. doi: 10.1016/j.ejmech.2020.112240. Epub 2020 Mar 17.

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.

Keywords: Glioblastoma inhibitor; Nuclear receptor; Spiro[pyrrolidine-3,3′-oxindole]; Structure-based drug design.

MeSH terms

  • Animals
  • Antineoplastic Agents / chemical synthesis
  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / pharmacology*
  • Cell Proliferation / drug effects
  • Cell Survival / drug effects
  • Dose-Response Relationship, Drug
  • Drug Discovery*
  • Drug Screening Assays, Antitumor
  • Glioblastoma / drug therapy*
  • Glioblastoma / metabolism
  • HEK293 Cells
  • Humans
  • Liver X Receptors / agonists*
  • Liver X Receptors / metabolism
  • Machine Learning
  • Male
  • Mice
  • Mice, Inbred BALB C
  • Mice, Nude
  • Molecular Structure
  • Neoplasms, Experimental / drug therapy
  • Neoplasms, Experimental / metabolism
  • Neoplasms, Experimental / pathology
  • Oxindoles / chemical synthesis
  • Oxindoles / chemistry
  • Oxindoles / pharmacology*
  • Pyrrolidines / chemical synthesis
  • Pyrrolidines / chemistry
  • Pyrrolidines / pharmacology*
  • Spiro Compounds / chemical synthesis
  • Spiro Compounds / chemistry
  • Spiro Compounds / pharmacology*
  • Structure-Activity Relationship
  • Tumor Cells, Cultured

Substances

  • Antineoplastic Agents
  • Liver X Receptors
  • Oxindoles
  • Pyrrolidines
  • Spiro Compounds
  • pyrrolidine