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

• Published in: Bioorganic & medicinal chemistry letters 2018-09, Vol.28 (16), p.2675-2678
• Main Authors: Anglin, Justin, Zavareh, Reza Beheshti, Sander, Philipp N., Haldar, Daniel, Mullarky, Edouard, Cantley, Lewis C., Kimmelman, Alec C., Lyssiotis, Costas A., Lairson, Luke L.
• Format: Article
• Language: English
• Subjects: Animals; Aspartate Aminotransferase, Cytoplasmic; Aspartate aminotransferase-1; Aspartate Aminotransferases - antagonists & inhibitors; Cancer metabolism; Carcinoma, Pancreatic Ductal - drug therapy; Drug Discovery; Drug Stability; Enzyme Inhibitors - chemical synthesis; Enzyme Inhibitors - chemistry; Enzyme Inhibitors - pharmacokinetics; Enzyme Inhibitors - therapeutic use; Female; Glutamic-oxaloacetic transaminase-1; Indoles - chemical synthesis; Indoles - chemistry; Indoles - pharmacokinetics; Indoles - therapeutic use; Inhibitor; Mice; Pancreatic ductal adenocarcinoma; Phenylurea Compounds - chemical synthesis; Phenylurea Compounds - chemistry; Phenylurea Compounds - pharmacokinetics; Phenylurea Compounds - therapeutic use; Piperazines - chemical synthesis; Piperazines - chemistry; Piperazines - pharmacokinetics; Piperazines - therapeutic use; Structure-Activity Relationship; Transaminases - antagonists & inhibitors
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2018.04.061

[Display omitted] •PDAC tumors are dependent on GOT1 for redox homeostasis and sustained proliferation.•4-(1H-Indol-4-yl)-N-phenylpiperazine-1-carboxamide is a GOT1 inhibitor.•Medicinal chemistry-based optimization resulted in the improvement of potency.•A tryptamine-based derivative series of GOT1 inhibitors was identified. 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.