2. Academic Validation
  3. Discovery and optimization of aspartate aminotransferase 1 inhibitors to target redox balance in pancreatic ductal adenocarcinoma

Discovery and optimization of aspartate aminotransferase 1 inhibitors to target redox balance in pancreatic ductal adenocarcinoma

  • Bioorg Med Chem Lett. 2018 Sep 1;28(16):2675-2678. doi: 10.1016/j.bmcl.2018.04.061.
Justin Anglin 1,  Reza Beheshti Zavareh 2,  Philipp N Sander 3,  Daniel Haldar 4,  Edouard Mullarky 5,  Lewis C Cantley 5,  Alec C Kimmelman 6,  Costas A Lyssiotis 7,  Luke L Lairson 8
Affiliations

Affiliations

  • 1 California Institute for Biomedical Research, 11119 North Torrey Pines Road, La Jolla, CA 92037, USA.
  • 2 California Institute for Biomedical Research, 11119 North Torrey Pines Road, La Jolla, CA 92037, USA; Department of Chemistry, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA.
  • 3 Department of Chemistry, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA.
  • 4 Department of Systems Biology, Harvard Medical School, Boston, MA 02215, USA.
  • 5 Meyer Cancer Center, Department of Medicine, Weill Cornell Medical College, New York, NY 10065, USA.
  • 6 Department of Radiation Oncology, Perlmutter Cancer Center, NYU Langone Medical Center, New York, NY 10016, USA.
  • 7 Department of Molecular and Integrative Physiology, University of Michigan Medical School, Ann Arbor, MI 48109, USA; Department of Internal Medicine, Division of Gastroenterology, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
  • 8 California Institute for Biomedical Research, 11119 North Torrey Pines Road, La Jolla, CA 92037, USA; Department of Chemistry, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA. Electronic address: llairson@scripps.edu.
PMID: 29731362 DOI: 10.1016/j.bmcl.2018.04.061
Abstract

Pancreatic ductal adenocarcinoma (PDAC) is a lethal malignancy that is extremely refractory to the therapeutic approaches that have been evaluated to date. Recently, it has been demonstrated that PDAC tumors are dependent upon a metabolic pathway involving aspartate aminotransferase 1, also known as glutamate-oxaloacetate transaminase 1 (GOT1), for the maintenance of redox homeostasis and sustained proliferation. As such, small molecule inhibitors targeting this metabolic pathway may provide a novel therapeutic approach for the treatment of this devastating disease. To this end, from a high throughput screen of ∼800,000 molecules, 4-(1H-indol-4-yl)-N-phenylpiperazine-1-carboxamide was identified as an inhibitor of GOT1. Mouse pharmacokinetic studies revealed that potency, rather than inherent metabolic instability, would limit immediate cell- and rodent xenograft-based experiments aimed at validating this potential Cancer metabolism-related target. Medicinal chemistry-based optimization resulted in the identification of multiple derivatives with >10-fold improvements in potency, as well as the identification of a tryptamine-based series of GOT1 inhibitors.

Keywords

Aspartate aminotransferase-1; Cancer metabolism; Glutamic-oxaloacetic transaminase-1; Inhibitor; Pancreatic ductal adenocarcinoma.

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