Related Experiment Video

Updated: Jan 4, 2026

Author Spotlight: Reprogramming Cancer Cells to iPSCs to Study Disease Progression and Treatment Targets
07:08

Author Spotlight: Reprogramming Cancer Cells to iPSCs to Study Disease Progression and Treatment Targets

Published on: February 2, 2024

1.3K

An allosteric PGAM1 inhibitor effectively suppresses pancreatic ductal adenocarcinoma

Chen-Lei Wen1,2, Ke Huang3, Lu-Lu Jiang3

  • 1Research Institute of Pancreatic Disease, Ruijin Hospital, School of Medicine, Shanghai Jiao Tong University, 200025 Shanghai, China.

Proceedings of the National Academy of Sciences of the United States of America
|October 31, 2019
PubMed

Insights

Researchers developed a novel phosphoglycerate mutase 1 (PGAM1) inhibitor, KH3, to target pancreatic ductal adenocarcinoma (PDAC). KH3 effectively suppressed PDAC cell proliferation by inhibiting key cancer metabolism pathways, showing promise for clinical application.

Area of Science:

  • Oncology
  • Biochemistry
  • Metabolic pathways

Background:

  • Pancreatic ductal adenocarcinoma (PDAC) is a deadly cancer with limited treatment options.
  • Phosphoglycerate mutase 1 (PGAM1) is a key glycolytic enzyme crucial for cancer cell growth and biosynthesis.
  • A validated PGAM1 inhibitor for PDAC treatment is currently lacking.

Purpose of the Study:

  • To develop and evaluate novel allosteric PGAM1 inhibitors for PDAC treatment.
  • To investigate the efficacy of PGAM1 inhibition in suppressing PDAC cell proliferation and metabolic activity.
  • To establish a potential therapeutic strategy targeting cancer metabolism in PDAC.

Main Methods:

  • Structure-guided optimization was used to design allosteric PGAM1 inhibitors.
  • The efficacy of the lead compound KH3 was assessed in various PDAC cell lines and patient-derived xenograft (PDX) models.
  • Correlation between PGAM1 expression levels and treatment response was analyzed in patient cohorts and PDX models.

Main Results:

  • Elevated PGAM1 expression correlated with worse prognosis in PDAC patients.
  • The developed inhibitor KH3 significantly suppressed PDAC cell proliferation by down-regulating glycolysis and mitochondrial respiration.
  • KH3 treatment mimicked PGAM1 depletion effects, hindering critical cancer metabolism and development pathways.
  • KH3 efficacy in PDX models was associated with higher PGAM1 expression and sustained metabolic pathway suppression.

Conclusions:

  • Targeting cancer metabolism via PGAM1 inhibition presents a viable therapeutic strategy for PDAC.
  • The study provides proof of concept for the clinical application of metabolic treatments in PDAC.
  • KH3 demonstrates significant potential as an anti-PDAC agent by disrupting essential metabolic processes.
Keywords:
PDACPGAM1 inhibitorcancer metabolismglycolysis

More Related Videos

Ultrasound-Guided Orthotopic Implantation of Murine Pancreatic Ductal Adenocarcinoma06:21

Ultrasound-Guided Orthotopic Implantation of Murine Pancreatic Ductal Adenocarcinoma

Published on: November 19, 2019

12.0K
Syngeneic Mouse Orthotopic Allografts to Model Pancreatic Cancer06:20

Syngeneic Mouse Orthotopic Allografts to Model Pancreatic Cancer

Published on: October 4, 2022

3.6K

Related Concept Videos

GPCRs Regulate Adenylyl Cylase Activity01:09

GPCRs Regulate Adenylyl Cylase Activity

Some GPCRs transmit signals through adenylyl cyclase (AC), a transmembrane enzyme. AC helps synthesize second messenger cyclic adenosine monophosphate (cAMP). AC catalyzes cyclization reaction and converts ATP to cAMP by releasing a pyrophosphate. The pyrophosphate is further hydrolyzed to phosphate by the enzyme pyrophosphatase, which drives cAMP synthesis to completion. However, cAMP is rapidly degraded to 5′ AMP by the enzymes phosphodiesterase (PDE), preventing overstimulation of...
7.1K
Dipeptidyl Peptidase 4 Inhibitors01:23

Dipeptidyl Peptidase 4 Inhibitors

Dipeptidyl peptidase 4 (DPP-4) is a serine protease widely distributed in the body. It's involved in the inactivation of GLP-1 and GIP hormones, which are crucial for insulin regulation. DPP-4 inhibitors, such as sitagliptin (Januvia), saxagliptin (Onglyza), linagliptin (Tradjenta), alogliptin (Nesina), and vildagliptin (Galvus), help increase the proportion of active GLP-1, enhancing insulin secretion. These inhibitors work by competitively binding to DPP-4. This binding causes a...
525
Glucagon-like Receptor Agonists01:24

Glucagon-like Receptor Agonists

Incretins include glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), which stimulate insulin secretion post-meals. In type 2 diabetes, GIP's efficacy is reduced, making GLP-1 a viable drug target. GIP originates from preproGIP.
GLP-1, when administered in high doses intravenously, triggers insulin secretion, inhibits glucagon release, slows gastric emptying, reduces food intake, and restores normal insulin secretion. However, its rapid inactivation by...
792
Chronic Pancreatitis I: Introduction01:24

Chronic Pancreatitis I: Introduction

The pancreas, an elongated and flat gland situated behind the stomach, serves a vital function in digesting food and managing blood sugar levels.
Pancreatitis is the inflammation of the pancreas, which occurs when the immune system becomes active and causes swelling, pain, and disruptions in organ function. Pancreatitis can manifest as either an acute or chronic condition.
Acute pancreatitis arises suddenly and lasts for a brief duration, while chronic pancreatitis is a long-term affliction...
639