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Discovery and optimization of pyrazolopyrimidine sulfamates as ATG7 inhibitors
Shih-Chung Huang1, Sharmila Adhikari1, James E Brownell1
1Takeda Pharmaceuticals International Co., 40 Landsdowne Street, Cambridge, MA 02139, United States.
Abstract:
Autophagy is postulated to be required by cancer cells to survive periods of metabolic and/or hypoxic stress. ATG7 is the E1 enzyme that is required for activation of Ubl conjugation pathways involved in autophagosome formation. This article describes the design and optimization of pyrazolopyrimidine sulfamate compounds as potent and selective inhibitors of ATG7. Cellular levels of the autophagy markers, LC3B and NBR1, are regulated following treatment with these compounds.
Insights
Researchers developed novel pyrazolopyrimidine sulfamates that inhibit ATG7, an enzyme crucial for autophagy. These compounds help cancer cells survive stress by regulating autophagy markers like LC3B.
Area of Science:
- Oncology
- Molecular Biology
- Biochemistry
Background:
- Autophagy is essential for cancer cell survival under metabolic or hypoxic stress.
- ATG7 acts as the E1 enzyme for ubiquitin-like protein conjugation, vital for autophagosome formation.
Purpose of the Study:
- To design and optimize potent and selective inhibitors of ATG7.
- To investigate the role of ATG7 inhibition in cancer cell survival mechanisms.
Main Methods:
- Medicinal chemistry for the design and synthesis of pyrazolopyrimidine sulfamate compounds.
- Biochemical assays to assess ATG7 inhibition.
- Cellular studies to measure autophagy markers (LC3B, NBR1).
Main Results:
- Novel pyrazolopyrimidine sulfamates were successfully designed and optimized as ATG7 inhibitors.
- Compounds demonstrated potent and selective inhibition of ATG7 activity.
- Treatment with these compounds led to the regulation of cellular autophagy markers LC3B and NBR1.
Conclusions:
- Pyrazolopyrimidine sulfamates are effective inhibitors of ATG7.
- Targeting ATG7 with these compounds offers a potential strategy for cancer therapy by modulating autophagy.
