An allosteric PGAM1 inhibitor effectively suppresses pancreatic ductal adenocarcinoma

Abstract

Significance Dysregulated metabolism is one of the hallmarks of pancreatic ductal adenocarcinoma, which is the major subtype of pancreatic cancer considered as the deadliest malignancy worldwide. This led us to search the potent therapeutic target for regulating cancer metabolism in treatment. By uncovering that phosphoglycerate mutase 1 (PGAM1), a critical metabolic enzyme involved in glycolysis and biosynthesis, was frequently up-regulated in patients with pancreatic ductal adenocarcinoma (PDAC), we developed a series of allosteric PGAM1 inhibitors which showed efficacious in multiple preclinical models of PDAC, especially with high PGAM1 expression. Of note, PGAM1 inhibition cosuppressed several metabolic and cancerous pathways, of which the suppression level was correlated with efficacy. This work strongly suggests that inhibition of cancer metabolism would be a strategy for treating pancreatic cancer. Glycolytic enzyme phosphoglycerate mutase 1 (PGAM1) plays a critical role in cancer metabolism by coordinating glycolysis and biosynthesis. A well-validated PGAM1 inhibitor, however, has not been reported for treating pancreatic ductal adenocarcinoma (PDAC), which is one of the deadliest malignancies worldwide. By uncovering the elevated PGAM1 expressions were statistically related to worse prognosis of PDAC in a cohort of 50 patients, we developed a series of allosteric PGAM1 inhibitors by structure-guided optimization. The compound KH3 significantly suppressed proliferation of various PDAC cells by down-regulating the levels of glycolysis and mitochondrial respiration in correlation with PGAM1 expression. Similar to PGAM1 depletion, KH3 dramatically hampered the canonic pathways highly involved in cancer metabolism and development. Additionally, we observed the shared expression profiles of several signature pathways at 12 h after treatment in multiple PDAC primary cells of which the matched patient-derived xenograft (PDX) models responded similarly to KH3 in the 2 wk treatment. The better responses to KH3 in PDXs were associated with higher expression of PGAM1 and longer/stronger suppressions of cancer metabolic pathways. Taken together, our findings demonstrate a strategy of targeting cancer metabolism by PGAM1 inhibition in PDAC. Also, this work provided “proof of concept” for the potential application of metabolic treatment in clinical practice.