Johns Hopkins Drug Discovery - Project - Glutaminase
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Glutaminase

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Kidney-type glutaminase (GLS) plays a critical role in glutaminolysis, an important energy source for all proliferating cells. In the nervous system, GLS serve 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 dementia1 and multiple sclerosis.2 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.3  In collaboration with Drs. Justin Hanes and Anne Le, we have developed a nanoparticle approach to formulate our BPTES to circumvent the poor solubility of BPTES.4 In another approach, we are conducting structural optimization using BPTES as a molecular template to improve its potency and drug-like molecular properties,5,6 which may have therapeutic utility in other disease areas. For example, as the Therapeutic Core of the Johns Hopkins NIMH Center for Novel Therapeutics for HIV-Associated Neurocognitive Disorders (HAND), JHDD is working closely with other cores of the center to explore the therapeutic utility of GLS inhibitors in HAND.

 

REFERENCES

  1. 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]
  2. 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]
  3. 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]
  4. Elgogary A, Xu Q, Poore B, Alt J, Zimmermann SC, Zhao L, Fu J, Chen B, Xia S, Liu Y, Neisser M, Nguyen C, Lee R, Park JK, Reyes J, Hartung T, Rojas C, Rais R, Tsukamoto T, Semenza GL, Hanes J, Slusher BS, Le A. “Combination therapy with BPTES nanoparticles and metformin targets the metabolic heterogeneity of pancreatic cancer.”  Proceedings of the National Academy of Sciences, 2016, Sep 6;113(36):E5328-36. [PubMed]
  5. Shukla K, Ferraris DV, Thomas AG, Stathis M, Duvall B, Delahanty G, Alt J, Rais R, Rojas C, Gao P, Xiang Y, Dang CV, Slusher BS, Tsukamoto T. Design, synthesis, and pharmacological evaluation of bis-2-(5-phenylacetamido-1,2,4-thiadiazol-2-yl)ethyl sulfide 3 (BPTES) analogs as glutaminase inhibitors. J Med Chem. 2012;55(23):10551-63. [PubMed]
  6. Zimmermann SC, Wolf EF, Luu A, Thomas AG, Stathis M, Poore B, Nguyen C, Le A, Rojas C, Slusher BS. “Allosteric glutaminase inhibitors based on a 1,4-Di(5-amino-1,3,4-thiadiazol-2-yl)butane scaffold.” ACS Med Chem Lett, 2016, Mar 13;7(5):520-4. [PubMed]