This research proposal aims to investigate the therapeutic utility of GLS inhibition in cancer chemotherapy. Evidence shows pancreatic cancer displays an increased dependence on glutaminolysis, which supports a number of crucial cellular pathways. Glutaminase (GLS), a key enzyme participating in glutaminolysis, catalyzes the hydrolysis of glutamine into glutamate. We have previously reported the antiproliferative effects of GLS inhibition on lymphoma B cells using an allosteric GLS inhibitor, bis-2-(5-phenylacetamido-1,3,4- thiadiazol-2-yl)ethyl sulfide (BPTES). In addition, BPTES was reported to show anti-tumor activity across a variety of tumor types. While BPTES offers some advantages over traditional glutaminase inhibitors, BPTES suffers from weak inhibitory potency and poor aqueous solubility (<10 g/mL), hindering its utility an anticancer agent. Further structural optimization to improve potency and solubility is essential for translating GLS inhibitors into therapeutic agents to treat pancreatic cancer. To perform this optimization, the following aims will be pursued: (1) Identify potent soluble GLS inhibitors with improved drug-like properties (2) Assess in vitro and in vivo antiproliferative effects of GLS inhibitors in pancreati cancer. Through analysis of our preliminary SAR data coupled with the recently published GLS crystal structure, the pharmacophore required for glutaminase inhibition has been evaluated to provide direction for the optimization of the BPTES scaffold. Based on our preliminary SAR data from BPTES analogs, the PI will conduct structural modifications to identify soluble and potent GLS inhibitors with improved drug-like properties. The synthesized compounds will be tested for their ability to inhibit GLS using recombinant human enzyme. Potent inhibitors will be tested for their metabolic stability followed by in vivo pharmacokinetics to select the best inhibitors for further studies to evaluate in vitro and in vivo anti-proliferative effects on pancreatic cancer.
The goal of the training research proposal is to identify small molecule inhibitors of kidney-type glutaminase (GLS) through systematic structure-activity relationship (SAR) studies. Potent GLS inhibitors identified from this project will have the potential to offer truly novel therapeutics for the treatment of pancreatic cancer.
|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|
|Ramachandran, Sarath; Pan, Catherine Qiurong; Zimmermann, Sarah C et al. (2016) Structural basis for exploring the allosteric inhibition of human kidney type glutaminase. Oncotarget 7:57943-57954|
|Zimmermann, Sarah C; Wolf, Emily F; Luu, Andrew et al. (2016) Allosteric Glutaminase Inhibitors Based on a 1,4-Di(5-amino-1,3,4-thiadiazol-2-yl)butane Scaffold. ACS Med Chem Lett 7:520-4|