1. Academic Validation
  2. Dimeric small molecule agonists of EphA2 receptor inhibit glioblastoma cell growth

Dimeric small molecule agonists of EphA2 receptor inhibit glioblastoma cell growth

  • Bioorg Med Chem. 2020 Sep 15;28(18):115656. doi: 10.1016/j.bmc.2020.115656.
Cody M Orahoske 1 Yaxin Li 1 Aaron Petty 2 Fatma M Salem 1 Jovana Hanna 1 Wenjing Zhang 1 Bin Su 3 Bingcheng Wang 4
Affiliations

Affiliations

  • 1 Department of Chemistry, Center for Gene Regulation in Health and Disease, College of Sciences & Health Professions, Cleveland State University, 2121 Euclid Ave., Cleveland, OH 44115, USA.
  • 2 Rammelkamp Center for Research and Department of Medicine, MetroHealth Campus, Case Comprehensive Cancer Center, Case Western Reserve University School of Medicine, Cleveland, OH, USA.
  • 3 Department of Chemistry, Center for Gene Regulation in Health and Disease, College of Sciences & Health Professions, Cleveland State University, 2121 Euclid Ave., Cleveland, OH 44115, USA. Electronic address: B.su@csuohio.edu.
  • 4 Rammelkamp Center for Research and Department of Medicine, MetroHealth Campus, Case Comprehensive Cancer Center, Case Western Reserve University School of Medicine, Cleveland, OH, USA. Electronic address: bxw14@case.edu.
Abstract

EphA2 receptor kinase could become a novel target for anti-glioblastoma treatment. Doxazosin previously identified acts like the endogenous ligand of EphA2 and induces cell Apoptosis. Through lead structure modification a derivative of Doxazosin possessing unique dimeric structure showed an improvement in the activity. In the current study, we expanded the dimeric scaffold by lead optimization to explore the chemical space of the conjoining moieties and a slight variation to the core structure. 27 new derivatives were synthesized and examined with EphA2 overexpressed and wild type glioblastoma cell lines for cell proliferation and EphA2 activation. Three new compounds 3d, 3e, and 7bg showed potent and selective activities against the growth of EphA2 overexpressed glioblastoma cells. Dimer 3d modification replaces the long alkyl chain with a short polyethylene glycol chain. Dimer 7bg has a relatively longer polyethylene glycol chain in comparison to compound 3d and the length is more similar to the lead compound. Whereas dimer 3e has a rigid aromatic linker exploring the chemical space. The diversity of the linkers in the active suggest additional hydrogen binding sites has a positive correlation to the activity. All three dimers showed selective activity in EphA2 overexpressed cells, indicating the activity is correlated to the EphA2 targeting effect.

Keywords

Agonist; Dimer; Doxazosin; EphA2; Glioblastoma.

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