Design, synthesis and biological evaluation of new glutaminase inhibitors
(2017)
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- Tumor cells depend strongly on the consumption of glutamine to produce energy, metabolites and to mitigate the oxidative stress linked to their intensive proliferation. Mammalian tissues express two isoforms of glutaminase. The kidney type (KGA) is coded by the GLS1 gene and the liver type is coded by GLS2. GLS1 has been shown to be overexpressed in tumor cells by the oncogenic transcription factor MYC. Bis-2-(5-phenylacetamido-1,2,4-thiadiazol-2-yl)ethyl sulfide (BPTES) is a potent and selective inhibitor of human kidney glutaminase (KGA). In an attempt to improve its potency and its pharmacological properties, BPTES analogs were synthesized and their cytotoxic activities were evaluated against the cancer cell line SiHa acclimated at low pH. First, a modification of the phenylacetamido moiety of BPTES was performed. Second, a modification of the linker moiety was performed. Finally, a modification of one of the heterocycle was carried out. Chronologically, at this point of the project, several references containing an important number of newly synthesized BPTES-derivatives were published. In total, the number of new compounds synthesized and evaluated was close to 1,000. Strategically, the decision was made to redirect the research project. Since all these former compounds belong to the BPTES family, there was a necessity to look for molecules possessing a new chemotype capable of inhibiting GLS1. The strategy chosen was to use the structural and biological data published to develop a docking model followed by a pharmacophore. The docking model was build, evaluated and used to determine the spatial orientation of known inhibitors of GLS1. This information allowed the development of a pharmacophore followed by a virtual screening of a large database composed of a large set of virtual compounds.
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Drozak, X. (2017). Design, synthesis and biological evaluation of new glutaminase inhibitors. https://hdl.handle.net/2078.5/62101