Discovery of new LXRβ agonists as glioblastoma inhibitors

Hao Chen; Ziyang Chen; Zizhen Zhang; Yali Li; Shushu Zhang; Fuqiang Jiang; Junkang Wei; Peng Ding; Huihao Zhou; Qiong Gu; Jun Xu

doi:10.1016/j.ejmech.2020.112240

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.

Authors

Hao Chen¹, Ziyang Chen¹, Zizhen Zhang¹, Yali Li¹, Shushu Zhang¹, Fuqiang Jiang¹, Junkang Wei¹, Peng Ding¹, Huihao Zhou², Qiong Gu³, Jun Xu⁴

Affiliations

¹ Guangdong 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.
² Guangdong 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. Electronic address: zhuihao@mail.sysu.edu.cn.
³ Guangdong 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. Electronic address: guqiong@mail.sysu.edu.cn.
⁴ Guangdong 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. Electronic address: junxu@biochemomes.com.

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

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