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

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.

Figure 1

HTS GOT1 inhibitor hit 1a.

Scheme 1

Synthesis of 1a, 1g–1i, 1l–1w, 2a–2j, 2l, 2n–2p, 2t–2as, 2aw, 2ba, 4c and 4f. Reagents and conditions: (i) 1.1 eq. TEA, DCM, R.T., 15m. 20–80%.

Scheme 2

Synthesis of 3a–j. Regents and conditions: (i) 1.1 eq. TEA, DCM, R.T., 30 minutes, 10–50%.