Glutaminase Inhibitors

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

Related Publication(s)

McDermott, L. A., Iyer, P., Vernetti, L., Rimer, S., Sun, J., Boby, M., Yang, T., Fioravanti, M., O’Neill, J., Wang, L., Drakes, D., Katt, W., Huang, Q., & Cerione, R. (2016). Design and evaluation of novel glutaminase inhibitors. Bioorganic & Medicinal Chemistry, 24(8), 1819–1839. https://doi.org/10.1016/j.bmc.2016.03.009

Huang, Q., Stalnecker, C., Zhang, C., McDermott, L. A., Iyer, P., O’Neill, J., Reimer, S., Cerione, R. A., & Katt, W. P. (2018). Characterization of the interactions of potent allosteric inhibitors with glutaminase C, a key enzyme in cancer cell glutamine metabolism. Journal of Biological Chemistry, 293(10), 3535–3545. https://doi.org/10.1074/jbc.m117.810101

McDermott, L., Koes, D., Mohammed, S., Iyer, P., Boby, M., Balasubramanian, V., Geedy, M., Katt, W., & Cerione, R. (2019). GAC inhibitors with a 4-hydroxypiperidine spacer: Requirements for potency. Bioorganic & Medicinal Chemistry Letters, 29(19), 126632. https://doi.org/10.1016/j.bmcl.2019.126632