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A Chemical Biology Approach to the C...

West, Thomas.

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A Chemical Biology Approach to the Cell Type Selective Killing of Glioblastoma Tumor Cells.

Record Type:	Electronic resources : Monograph/item
Title/Author:	A Chemical Biology Approach to the Cell Type Selective Killing of Glioblastoma Tumor Cells./
Author:	West, Thomas.
Published:	Ann Arbor : ProQuest Dissertations & Theses, : 2024,
Description:	123 p.
Notes:	Source: Dissertations Abstracts International, Volume: 85-07, Section: B.
Contained By:	Dissertations Abstracts International85-07B.
Subject:	Chemistry. -
Online resource:	https://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=30988457
ISBN:	9798381379730

A Chemical Biology Approach to the Cell Type Selective Killing of Glioblastoma Tumor Cells.
West, Thomas.

A Chemical Biology Approach to the Cell Type Selective Killing of Glioblastoma Tumor Cells. - Ann Arbor : ProQuest Dissertations & Theses, 2024 - 123 p.

Source: Dissertations Abstracts International, Volume: 85-07, Section: B.

Thesis (Ph.D.)--The Scripps Research Institute, 2024.

This item must not be sold to any third party vendors.

Glioblastoma (GBM) remains virtually incurable; nearly all patients experience tumor progression with a median survival rate of less than 15 months1 . GBM's aggressive infiltration of the brain has been attributed to a specific sub population of cells termed cancer stem-like cells (CSC). Previously, the Lairson Lab identified a small molecule, RIPGBM, capable of driving GBM CSCs into apoptosis in a cell-type selective manner. The selectivity was proposed to derive from a unique pro-drug activation mechanism in which the molecule cyclized into an active derivative termed cRIPGBM which was found to be selectively formed in GBM CSCs. The molecular target of cRIPGBM was identified as Receptor Interacting Protein Kinase 2 (RIPK2)2 . Based on its structural similarity, the clinically used drug YM155 was subsequently evaluated for its ability bind RIPK2. This prompted the hypothesis that small molecule prodrugs that target RIPK2 are selectively activated in the tumor microenvironment, lead to cell type selective induction of apoptosis in GBM CSC's, and inhibit tumor growth in relevant rodent models.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 characterization 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 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.

ISBN: 9798381379730Subjects--Topical Terms:

516420
Chemistry.
Subjects--Index Terms:

Glioblastoma

A Chemical Biology Approach to the Cell Type Selective Killing of Glioblastoma Tumor Cells.
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500 $a Source: Dissertations Abstracts International, Volume: 85-07, Section: B.
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502 $a Thesis (Ph.D.)--The Scripps Research Institute, 2024.
506 $a This item must not be sold to any third party vendors.
520 $a Glioblastoma (GBM) remains virtually incurable; nearly all patients experience tumor progression with a median survival rate of less than 15 months1 . GBM's aggressive infiltration of the brain has been attributed to a specific sub population of cells termed cancer stem-like cells (CSC). Previously, the Lairson Lab identified a small molecule, RIPGBM, capable of driving GBM CSCs into apoptosis in a cell-type selective manner. The selectivity was proposed to derive from a unique pro-drug activation mechanism in which the molecule cyclized into an active derivative termed cRIPGBM which was found to be selectively formed in GBM CSCs. The molecular target of cRIPGBM was identified as Receptor Interacting Protein Kinase 2 (RIPK2)2 . Based on its structural similarity, the clinically used drug YM155 was subsequently evaluated for its ability bind RIPK2. This prompted the hypothesis that small molecule prodrugs that target RIPK2 are selectively activated in the tumor microenvironment, lead to cell type selective induction of apoptosis in GBM CSC's, and inhibit tumor growth in relevant rodent models.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 characterization 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 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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