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Published on: March 10, 2017
Discovery of Novel Small Molecule Inhibitors of VEGF Expression in Tumor Cells Using a Cell-Based High Throughput
Liangxian Cao1, Marla Weetall1, Jenelle Bombard1
1PTC Therapeutics, Inc., South Plainfield, New Jersey, United States of America.
Abstract:
Current anti-VEGF (Vascular Endothelial Growth Factor A) therapies to treat various cancers indiscriminately block VEGF function in the patient resulting in the global loss of VEGF signaling which has been linked to dose-limiting toxicities as well as treatment failures due to acquired resistance. Accumulating evidence suggests that this resistance is at least partially due to increased production of compensatory tumor angiogenic factors/cytokines. VEGF protein production is differentially controlled depending on whether cells are in the normal "homeostatic" state or in a stressed state, such as hypoxia, by post-transcriptional regulation imparted by elements in the 5' and 3' untranslated regions (UTR) of the VEGF mRNA. Using the Gene Expression Modulation by Small molecules (GEMS™) phenotypic assay system, we performed a high throughput screen to identify low molecular weight compounds that target the VEGF mRNA UTR-mediated regulation of stress-induced VEGF production in tumor cells. We identified a number of compounds that potently and selectively reduce endogenous VEGF production under hypoxia in HeLa cells. Medicinal chemistry efforts improved the potency and pharmaceutical properties of one series of compounds resulting in the discovery of PTC-510 which inhibits hypoxia-induced VEGF expression in HeLa cells at low nanomolar concentration. In mouse xenograft studies, oral administration of PTC-510 results in marked reduction of intratumor VEGF production and single agent control of tumor growth without any evident toxicity. Here, we show that selective suppression of stress-induced VEGF production within tumor cells effectively controls tumor growth. Therefore, this approach may minimize the liabilities of current global anti-VEGF therapies.
Insights
New compounds selectively inhibit stress-induced Vascular Endothelial Growth Factor A (VEGF) production in tumor cells. This targeted approach reduces tumor growth and may overcome resistance associated with current broad anti-VEGF therapies.
Area of Science:
- Oncology
- Molecular Biology
- Drug Discovery
Background:
- Current anti-VEGF therapies globally inhibit VEGF signaling, leading to toxicities and treatment resistance.
- Tumor resistance to anti-VEGF therapy is often linked to increased compensatory angiogenic factors.
- VEGF production is regulated post-transcriptionally via untranslated regions (UTRs) of its mRNA, especially under cellular stress like hypoxia.
Purpose of the Study:
- To identify small molecules targeting VEGF mRNA UTRs to selectively inhibit stress-induced VEGF production in tumor cells.
- To develop novel anti-cancer agents that overcome limitations of current global anti-VEGF therapies.
Main Methods:
- High-throughput screening using the Gene Expression Modulation by Small molecules (GEMS™) assay.
- Identification and medicinal chemistry optimization of lead compounds.
- In vitro testing in HeLa cells under hypoxic conditions.
- In vivo efficacy and toxicity studies in mouse xenograft models.
Main Results:
- A novel compound series was identified that selectively reduces hypoxia-induced VEGF production in HeLa cells.
- PTC-510 emerged as a potent inhibitor, effective at low nanomolar concentrations.
- Oral administration of PTC-510 in mouse xenografts significantly reduced intratumor VEGF and controlled tumor growth without apparent toxicity.
Conclusions:
- Selective suppression of stress-induced VEGF production is a viable strategy for tumor growth control.
- This targeted approach holds potential to minimize toxicities and overcome resistance associated with current global anti-VEGF therapies.
