6K9H

Human LXR-beta in complex with an agonist

Summary for 6K9H

• Entry DOI: 10.2210/pdb6k9h/pdb
• Descriptor: Oxysterols receptor LXR-beta, ~{tert}-butyl (2'~{S},3~{S})-2-oxidanylidene-2'-phenyl-spiro[1~{H}-indole-3,3'-pyrrolidine]-1'-carboxylate (3 entities in total)
• Functional Keywords: nuclear receptor, dna binding protein
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 2
• Total formula weight: 63072.05

Authors

Zhang, Z.,Zhou, H. (deposition date: 2019-06-15, release date: 2020-04-22, Last modification date: 2023-11-22)

Primary citation

Chen, H.,Chen, Z.,Zhang, Z.,Li, Y.,Zhang, S.,Jiang, F.,Wei, J.,Ding, P.,Zhou, H.,Gu, Q.,Xu, J.
Discovery of new LXR beta agonists as glioblastoma inhibitors.
Eur.J.Med.Chem., 194:112240-112240, 2020

PubMed 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 IC 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.

PubMed: 32248003
DOI: 10.1016/j.ejmech.2020.112240

Experimental method

X-RAY DIFFRACTION (2.5 Å)