期刊
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
卷 145, 期 15, 页码 8355-8363出版社
AMER CHEMICAL SOC
DOI: 10.1021/jacs.2c11715
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In this study, a prodrug form of YM155 called aYM155 was designed, synthesized, and characterized. aYM155 displayed potent cell killing activity against GBM and EGFRvIII-expressing cells, and was activated in a cell-type-dependent manner. It was also found that YM155 interacted with receptor-interacting protein kinase 2 (RIPK2) and exhibited survivin-suppressing and apoptosis-inducing activities. In an orthotopic intracranial GBM xenograft model, aYM155 significantly inhibited brain tumor growth and showed cell-type selective survivin-based pharmacodynamic effects.
Glioblastoma (GBM) is the most prevalent and aggressive primary central nervous system (CNS) malignancy. YM155 is a highly potent broad-spectrum anti-cancer drug that was derived from a phenotypic screen for functional inhibitors of survivin expression, but for which the relevant biomolecular target remains unknown. Presumably as a result of its lack of cell-type selectivity, YM155 has suffered from tolerability issues in the clinic. Based on its structural similarity to the GBM-selective prodrug RIPGBM, here, we report the design, synthesis, and character-ization of a prodrug form of YM155, termed aYM155. aYM155 displays potent cell killing activity against a broad panel of patient-derived GBM cancer stem-like cells (IC50 = 0.7-10 nM), as well as EGFR-amplified and EGFR variant III-expressing (EGFRvIII) cell lines (IC50 = 3.8-36 nM), and becomes activated in a cell-type-dependent manner. Mass spectrometry-based analysis indicates that enhanced cell-type selectivity results from relative rates of prodrug activation in transformed versus non-transformed cell types. The prodrug strategy also facilitates transport into the brain (brain-to-plasma ratio, aYM155 = 0.56; YM155 = BLQ). In addition, we determine that the survivin-suppressing and apoptosis-inducing activities of YM155 involve its interaction with receptor-interacting protein kinase 2 (RIPK2). In an orthotopic intracranial GBM xenograft model, aYM155 prodrug significantly inhibits brain tumor growth in vivo, which correlates with cell-type selective survivin-based pharmacodynamic effects.
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