A recent genome wide analysis revealed that approximately 80% of grade II-III gliomas and secondary glioblasotomas harbor mutations in cytosolic isocitrate dehydrogenase 1 (IDH1). Subsequent studies revealed that the mutant IDH1 gained a new function, conversion of alpha- ketoglutarate to 2-hydroxyglutarate. Thus, alpha-ketoglutarate produced by wild-type IDH1 is consumed by the mutant IDH1, depleting cells of alpha-ketoglutarate. We hypothesized that cells with mutant IDH1 may be more susceptible to blockade of glutaminolysis, which plays a critical role in proliferation of tumor cells by serving as an alternative source of alpha-ketoglutarate. To test this hypothesis, the following aims will be pursued:
Aim 1.) Identify potent soluble GLS inhibitors with improved drug-like molecular properties;
Aim 2.) Assess antiproliferative effects of GLS inhibitors in D54 glioblastoma cell lines. Upon completion of this project, we expect to identify new GLS inhibitors with more drug-like molecular properties, which can serve as therapeutic prototypes to establish in vivo proof-of-concept in animal models of glioma in future.

Public Health Relevance

The goal of the proposed research is to conduct systematic SAR (structure-activity relationships) studies to identify kidney-type glutaminase (GLS) inhibitors as small molecule probes for evaluating the therapeutic utility of GLS inhibition in glioma with IDH (isocitrate dehydrogenase) mutations. New GLS inhibitors emerging from this project will be tested in comparative cell growth studies using D54 glioblastoma cell lines constitutively overexpressing either wild-type or mutant R132H IDH1. These studies should lead to the discovery of new GLS inhibitors with more drug-like properties, which can serve as therapeutic prototypes in future experiments to establish in vivo proof-of-concept in animal models of glioma.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Exploratory/Developmental Grants (R21)
Project #
Application #
Study Section
Special Emphasis Panel (ZRG1-MDCN-C (58))
Program Officer
Farkas, Rebecca M
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Johns Hopkins University
Schools of Medicine
United States
Zip Code
Elgogary, Amira; Xu, Qingguo; Poore, Brad et al. (2016) Combination therapy with BPTES nanoparticles and metformin targets the metabolic heterogeneity of pancreatic cancer. Proc Natl Acad Sci U S A 113:E5328-36
Emadi, Ashkan; Jun, Sung Ah; Tsukamoto, Takashi et al. (2014) Inhibition of glutaminase selectively suppresses the growth of primary acute myeloid leukemia cells with IDH mutations. Exp Hematol 42:247-51
Yang, Lifeng; Moss, Tyler; Mangala, Lingegowda S et al. (2014) Metabolic shifts toward glutamine regulate tumor growth, invasion and bioenergetics in ovarian cancer. Mol Syst Biol 10:728
Thomas, Ajit G; Rojas, Camilo; Tanega, Cordelle et al. (2013) Kinetic characterization of ebselen, chelerythrine and apomorphine as glutaminase inhibitors. Biochem Biophys Res Commun 438:243-8
Long, Yan; Tsai, Wen-Bin; Wangpaichitr, Medhi et al. (2013) Arginine deiminase resistance in melanoma cells is associated with metabolic reprogramming, glucose dependence, and glutamine addiction. Mol Cancer Ther 12:2581-90
Dutta, Prasanta; Le, Anne; Vander Jagt, David L et al. (2013) Evaluation of LDH-A and glutaminase inhibition in vivo by hyperpolarized 13C-pyruvate magnetic resonance spectroscopy of tumors. Cancer Res 73:4190-5
Yuneva, Mariia O; Fan, Teresa W M; Allen, Thaddeus D et al. (2012) The metabolic profile of tumors depends on both the responsible genetic lesion and tissue type. Cell Metab 15:157-70
Le, Anne; Lane, Andrew N; Hamaker, Max et al. (2012) Glucose-independent glutamine metabolism via TCA cycling for proliferation and survival in B cells. Cell Metab 15:110-21
Shukla, Krupa; Ferraris, Dana V; Thomas, Ajit G et al. (2012) 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 55:10551-63