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 (eCF309 to eCF334) for their antiproliferative properties in the nM range. These results were validated in patient-derived glioma 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.
Highlights
Glioblastoma multiforme (GBM) is the most common and aggressive cancer that begins within the brain
This space is rich in bioactive compounds that have been shown to target a variety of protein, lipid and atypical kinases,[11,12,13,14,15,16,17] improving the chances of finding active hits against glioma cells while facilitating the interpretation of potential structure activity relationship (SAR)
Strong synergistic activity was observed in most combinations, with maximum synergy found at 100 nM of eCF309 and 300 nM of GDC0941 in T98 cells. Since both compounds are known to be selective inhibitors of mTOR12 and PI3K,20 respectively, this study indicates that concurrent inhibition of mTOR and PI3Ks potentiate an antiproliferative effect in these two glioma cell lines
Summary
Glioblastoma multiforme (GBM) is the most common and aggressive cancer that begins within the brain. Phenotypic screening campaigns are the major source of first-inclass drugs that eventually reach the clinic.[4] In contrast to target-centric strategies, these cell-based compound screens survey changes in the cell phenotype, thereby embracing the complexity of the cell as a whole. This is especially important in cancer since redundancy, compensatory mechanisms, pathway cross-talks and plasticity are common and hardly predictable. This combination is currently in clinical phase.[7]
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