Kidney-type glutaminase (GLS) plays a critical role in glutaminolysis, an important energy source for all proliferating cells. Previously, we have reported the antiproliferative effects of an allosteric GLS inhibitor, BPTES, in lymphoma B cells in vitro and in vivo using a tumor xenograft model (1).To circumvent the poor solubility and druggability of BPTES, in collaboration with Dr. Justin Hanes and Dr. Anne Le, we have developed a nanoparticle approach to formulate our glutaminase inhibitors for a number of anticancer applications. Moreover, in the brain, GLS has a critical role as a source of glutamate, a key excitatory neurotransmitter, which is believed to play a key pathogenic role in neuroinflammatory disorders such as HIV1-associated dementia(2) and multiple sclerosis(3). Our team is currently pursuing brain-penetrable GLS inhibitors as new therapeutic agents for these conditions.
1. Le A, Lane AN, Hamaker M, Bose S, Gouw A, Barbi J, Tsukamoto T, Rojas CJ, Slusher BS, Zhang H, Zimmerman LJ, Liebler DC, Slebos RJ, Lorkiewicz PK, Higashi RM, Fan TW, Dang CV. Glucose-independent glutamine metabolism via TCA cycling for proliferation and survival in B cells. Cell Metab. 2012;15(1):110-21. [PubMed]
2. Erdmann NB, Whitney NP, Zheng J. Potentiation of Excitotoxicity in HIV-1 Associated Dementia and the Significance of Glutaminase. Clin Neurosci Res. 2006;6(5):315-28. [PubMed].
3. Shijie J, Takeuchi H, Yawata I, Harada Y, Sonobe Y, Doi Y, Liang J, Hua L, Yasuoka S, Zhou Y, Noda M, Kawanokuchi J, Mizuno T, Suzumura A. Blockade of glutamate release from microglia attenuates experimental autoimmune encephalomyelitis in mice. Tohoku J Exp Med. 2009;217(2):87-92. [PubMed].