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Publication Abstract from PubMed

Discovery and optimization of selective liver X receptor beta (LXRbeta) agonists are challenging due to the high homology of LXRalpha and LXRbeta 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, LXRbeta selective agonists were designed and synthesized. This led to the discovery of LXRbeta agonists 4-7rr, 4-13 and 4-13rr with IC50 values ranging from 1.78 to 6.36 muM 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.

Discovery of new LXRbeta agonists as glioblastoma inhibitors.,Chen H, Chen Z, Zhang Z, Li Y, Zhang S, Jiang F, Wei J, Ding P, Zhou H, Gu Q, Xu J Eur J Med Chem. 2020 May 15;194:112240. doi: 10.1016/j.ejmech.2020.112240. Epub, 2020 Mar 17. PMID:32248003^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.