Strategic Design and Development of Indole-Based Compounds as Potent Malic Enzyme 3 Inhibitors for Pancreatic Tumor Therapy.

Malic enzyme 3 (ME3) plays a critical role in the survival of SMAD4-/-/ME2-/- pancreatic ductal adenocarcinoma (PDAC) cells by supporting energy production and maintaining redox homeostasis. Therefore, targeting ME3 with small-molecule inhibitors presents a promising therapeutic strategy for PDAC patients with SMAD4/ME2 deletions. Building upon our previously developed ME3 inhibitor, a systematic exploration of the structure-activity relationship (SAR) was undertaken to identify novel chemotypes. This effort led to the discovery of a new series of indole-substituted piperazine carboxamides with potent ME3 inhibitory activity, among which compound 13 emerged to be the most effective in PDAC cell lines. Furthermore, the synergistic effects of the newly identified compound 13 with the mitogen-activated protein kinase kinase (MEK) inhibitor trametinib were evaluated on Hs766T cells which revealed a significant synergism of this combination.