Pyrazolopyrimide library screening in glioma cells discovers highly potent antiproliferative leads that target the PI3K/mTOR pathway

Maria Valero Grinan, Daniel Baillache, Craig Fraser, Samuel Myers, Asier Unciti-Broceta

Research output: Contribution to journalArticlepeer-review

Abstract


The search for novel targeted inhibitors active on glioblastoma multiforme is crucial to develop new treatments for this unmet clinical need. Herein, we report the results from a screening campaign against glioma cell lines using a proprietary library of 100 structurally-related pyrazolopyrimidines. Data analysis identified a family of compounds featuring a 2-amino-1,3-benzoxazole moiety (eCF307 to eCF334) for their antiproliferative properties in the nM range. These results were validated in patient-derived cells. Available kinase inhibition profile pointed to blockade of the PI3K/mTOR pathway as being responsible for the potent activity of the hits. Combination studies demonstrated synergistic activity by inhibiting both PI3Ks and mTOR with selective inhibitors. Based on the structure activity relationships identified in this study, five new derivatives were synthesized and tested, which exhibited potent activity against glioma cells but not superior to the dual PI3K/mTOR inhibitor and lead compound of the screening eCF324.
Original languageEnglish
JournalBioorganic and Medicinal Chemistry
Early online date25 Nov 2019
DOIs
Publication statusE-pub ahead of print - 25 Nov 2019

Keywords

  • Phenotypic Screening
  • Ligand-based drug discovery
  • Kinase inhibitors
  • Pyrazolopyrimidines
  • Anticancer drugs

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