An allosteric PGAM1 inhibitor effectively suppresses pancreatic ductal adenocarcinoma

Abstract

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.

Metabolomics identified new biomarkers for the precise diagnosis of pancreatic cancer and associated tissue metastasis

“…Pancreatic cancer (PC) is a malignant tumour in the clinic; although the disease occurrence rate is quite low, it is still likely to become the second leading cause of cancer-related death worldwide due to the extremely low 5-year survival rate of less than 5% [1][2][3] . Basically, the high mortality of patients with PC is attributed to the complex pathogenesis, and latency leads to a severe lack of early diagnostic methods.…”

“…Cancers are typical metabolic diseases whose development indeed incurs substantial metabolic alterations 1,10 . The Warburg effect is defined as the overexpression of aerobic glycolysis in cancer cells that can shunt glycolytic intermediates into multiple metabolic pathways that generate nucleotides, lipids, and amino acids 11 .…”

Glycometabolic rearrangements--aerobic glycolysis in pancreatic cancer: causes, characteristics and clinical applications

“…Phosphoglycerate mutase (PGAM) displays relatively high expression and activities in many malignant cancers, including PDAC. Via proteomic techniques, PGAM-1 is statistically indicated to be associated with a relatively poor prognosis in PDAC [ 152 ]. After knockdown of PGAM-1 expression, decreased glycolytic flux and reduced cell invasion were observed by detecting 3-PG and 2-PG levels and performing invasion experiments, respectively, but the association with proliferation was independent [ 36 ].…”

“…Therefore, targeting PTMs, such as dephosphorylation and deacetylation, at some sites in PGAM-1 could attenuate PGAM-1 enzymatic activity and tumorigenesis for PDAC treatment. Recently, a newly developed and promising compound, KH3, was found to act as an allosteric suppressor of PGAM-1, showing satisfactory drug effects to downregulate glycolysis and cell proliferation with limited cytotoxicity to PDAC cells [ 152 ].…”

<p>Phosphoglycerate Mutase 1: Its Glycolytic and Non-Glycolytic Roles in Tumor Malignant Behaviors and Potential Therapeutic Significance</p>

“…Huang et al 51 revealed that F22, K100, and R116 of PGAM1 residues were critical for the binding of inhibitors and that compound 9i, an anthraquinone inhibitor, significantly decreased lung cancer cell proliferation in different cell lines, which is a promising inhibitor for PGAM1. Moreover, in the recent research of Wen CL et al 55 an allosteric inhibitor of PGAMI named KH3 has been explored that dramatically inhibited the proliferation of PDAC cell lines by hampering the canonical cancer metabolic pathways. In summary, inhibitors targeting PGAM1 have been developed rapidly.…”