GAC inhibitors with a 4-hydroxypiperidine spacer: Requirements for potency |
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| Authors: | Lee McDermott David Koes Shabber Mohammed Prema Iyer Melissa Boby Venkatakrishnan Balasubramanian Mackenzie Geedy William Katt Richard Cerione |
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| Affiliation: | 1. University of Pittsburgh, Department of Pharmaceutical Sciences, Pittsburgh, PA 15260, USA;2. University of Pittsburgh, Drug Discovery Institute, Pittsburgh, PA 15269, USA;3. University of Pittsburgh, Department of Computational and Systems Biology, Pittsburgh, PA 15260, USA;4. SASTRA Deemed University, Department of Chemical Engineering, Tamil Nadu, Tirumalaisamudram, 613401, India;5. Cornell University, Department of Molecular Medicine, Ithaca, NY 14853, USA;6. Cornell University, Cornell High Energy Synchrotron Source (CHESS), Ithaca, NY 14853, USA;7. Cornell University, Department of Chemistry and Chemical Biology, Ithaca, NY 14853, USA |
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| Abstract: | Allosteric inhibitors of glutaminase (GAC), such as BPTES, CB-839 and UPGL00019, have great promise as inhibitors of cancer cell growth, but potent inhibitors with drug-like qualities have been difficult to achieve. Here, a small library of GAC inhibitors based on the UPGL00019 core is described. This set of derivatives was designed to assess if one or both of the phenylacetyl groups flanking the UPGL00019 core can be replaced by smaller simple aliphatic acyl groups without loss in potency. We found that one of the phenylacetyl moieties can be replaced by a set of small aliphatic moieties without loss in potency. We also found that enzymatic potency co-varies with the VDW volume or the maximum projection area of the groups used as replacements of the phenylacetyl moiety and used literature X-ray data to provide an explanation for this finding. |
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| Keywords: | Corresponding author at: University of Pittsburgh, Department of Pharmaceutical Sciences, Pittsburgh, PA 15260, USA. GAC UPGL00019 CB-839 UPGL00019 derivatives Novel glutaminase inhibitors BPTES |
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