Kidney-type glutaminase is a key player in the altered metabolic pathways of tumor cells. Upregulation of its GAC isoform and high utilization of its substrate glutamine are seen in a number of cancer cell lines. High glutamine utilization and dependence by cancer cells has been well-documented and is referred to as “glutamine addiction.” Inhibition of glutaminase through antisense, siRNA, and small molecule inhibitors has been shown to lead to a reduction in tumor cell proliferation as well as tumor size reduction in mice and is a promising approach to fighting cancer.
Description
A novel series of small molecule inhibitors of kidney-type glutaminase was designed and synthesized. The series includes derivatives with excellent drug-like properties and potency when compared to leading literature compounds. Outstanding in vivo tumor growth inhibition has been demonstrated by treating mice implanted with patient-derived triple negative breast cancer tumor grafts with low doses of a compound from our series in combination with bevacizumab. These compounds starve cancer cells of the glutamine they need to survive and proliferate, and offer a promising new tool in the fight against cancer.
Applications
· Inhibition/treatment of cancers dependent on glutamine
· Inhibition/treatment of triple negative breast cancer
· Combination regiments with other chemotherapeutics
Advantages
· Ease of synthesis that allows for quick expansion of the pool of available compounds and further optimization
· Excellent drug-like properties, metabolic stability, and potency.
Invention Readiness
In vivo data
IP Status
https://patents.google.com/patent/US10245254B2
