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.

胰腺导管腺癌（PDAC）是一种致命的恶性肿瘤，对迄今已评估的治疗方法极为难治。最近，已经证明PDAC肿瘤依赖于涉及天冬氨酸转氨酶1（也称为谷氨酸-草酰乙酸转氨酶1（GOT1））的代谢途径来维持氧化还原稳态和持续增殖。这样，靶向该代谢途径的小分子抑制剂可以提供用于治疗这种破坏性疾病的新颖的治疗方法。为此，从约800,000个分子的高通量筛选中，4-（1 H-吲哚-4-基）-N-苯基哌嗪-1-甲酰胺被鉴定为GOT1的抑制剂。小鼠药代动力学研究表明，效价而非固有的代谢不稳定性将限制旨在验证该潜在的癌症代谢相关靶点的基于细胞和啮齿动物异种移植的直接实验。基于药物化学的最优化导致鉴定出多种衍生物，其效力提高了10倍以上，并且鉴定了基于色胺的一系列GOT1抑制剂。