Jove
Visualize
Contact Us
JoVE
x logofacebook logolinkedin logoyoutube logo
ABOUT JoVE
OverviewLeadershipBlogJoVE Help Center
AUTHORS
Publishing ProcessEditorial BoardScope & PoliciesPeer ReviewFAQSubmit
LIBRARIANS
TestimonialsSubscriptionsAccessResourcesLibrary Advisory BoardFAQ
RESEARCH
JoVE JournalMethods CollectionsJoVE Encyclopedia of ExperimentsArchive
EDUCATION
JoVE CoreJoVE BusinessJoVE Science EducationJoVE Lab ManualFaculty Resource CenterFaculty Site
Terms & Conditions of Use
Privacy Policy
Policies

Related Concept Videos

  1. Home
  3. Research Domains
  5. Biomedical And Clinical Sciences
  7. Oncology And Carcinogenesis
  9. Predictive And Prognostic Markers
  11. Synthesis And Biological Characterization Of An Orally Bioavailable Lactate Dehydrogenase-a Inhibitor Against Pancreatic Cancer.
  1. Home
  3. Research Domains
  5. Biomedical And Clinical Sciences
  7. Oncology And Carcinogenesis
  9. Predictive And Prognostic Markers
  11. Synthesis And Biological Characterization Of An Orally Bioavailable Lactate Dehydrogenase-a Inhibitor Against Pancreatic Cancer.

Related Experiment Video

Bioluminescent Orthotopic Model of Pancreatic Cancer Progression
09:25

Bioluminescent Orthotopic Model of Pancreatic Cancer Progression

Published on: June 28, 2013

26.9K

Synthesis and biological characterization of an orally bioavailable lactate dehydrogenase-A inhibitor against pancreatic cancer.

Horrick Sharma1, Somrita Mondal1, Uzziah Urquiza2

  • 1Department of Pharmaceutical Sciences, College of Pharmacy, Southwestern Oklahoma State University, Weatherford, OK, USA.

European Journal of Medicinal Chemistry
|June 26, 2024

View abstract on PubMed

Summary
This summary is machine-generated.

Novel succinic acid monoamide inhibitors targeting lactate dehydrogenase-A (LDHA) show promise for pancreatic cancer treatment. These compounds exhibit potent inhibition, reduce cancer cell glycolysis, and possess favorable pharmacokinetic properties for potential drug development.

Keywords:
LactateLactate Dehydrogenase-AOXPHOSPancreatic cancer

More Related Videos

Utilizing 18F-FDG PET/CT Imaging and Quantitative Histology to Measure Dynamic Changes in the Glucose Metabolism in Mouse Models of Lung Cancer
06:51

Utilizing 18F-FDG PET/CT Imaging and Quantitative Histology to Measure Dynamic Changes in the Glucose Metabolism in Mouse Models of Lung Cancer

Published on: July 21, 2018

17.9K
Mapping Metabolism: Monitoring Lactate Dehydrogenase Activity Directly in Tissue
06:18

Mapping Metabolism: Monitoring Lactate Dehydrogenase Activity Directly in Tissue

Published on: June 21, 2018

11.4K

Related Experiment Videos

Bioluminescent Orthotopic Model of Pancreatic Cancer Progression
09:25

Bioluminescent Orthotopic Model of Pancreatic Cancer Progression

Published on: June 28, 2013

26.9K
Utilizing 18F-FDG PET/CT Imaging and Quantitative Histology to Measure Dynamic Changes in the Glucose Metabolism in Mouse Models of Lung Cancer
06:51

Utilizing 18F-FDG PET/CT Imaging and Quantitative Histology to Measure Dynamic Changes in the Glucose Metabolism in Mouse Models of Lung Cancer

Published on: July 21, 2018

17.9K
Mapping Metabolism: Monitoring Lactate Dehydrogenase Activity Directly in Tissue
06:18

Mapping Metabolism: Monitoring Lactate Dehydrogenase Activity Directly in Tissue

Published on: June 21, 2018

11.4K

Area of Science:

  • Biochemistry
  • Oncology
  • Medicinal Chemistry

Background:

  • Lactate dehydrogenase-A (LDHA) is overexpressed in pancreatic ductal adenocarcinoma (PDAC), correlating with poor patient survival.
  • Existing LDHA inhibitors face challenges due to suboptimal structural, physicochemical, and pharmacokinetic properties, hindering clinical translation.

Purpose of the Study:

  • To synthesize and biologically evaluate a novel class of LDHA inhibitors based on a succinic acid monoamide scaffold.
  • To investigate the therapeutic potential of these inhibitors in pancreatic cancer models.

Main Methods:

  • Synthesis of succinic acid monoamide derivatives and evaluation of their inhibitory activity against LDHA.
  • Cocrystallization of an inhibitor with LDHA to elucidate the binding mode.
Pharmacokinetics
Small molecule inhibitor
  • Assessment of cellular effects, including lactate production and glycolysis inhibition in pancreatic cancer cells.
  • Evaluation of antiproliferative activity in cancer cell lines and patient-derived organoids.
  • Pharmacokinetic studies in mice.

    • Main Results:

    • Compounds 6 and 21 demonstrated potent LDHA inhibition (IC50s of 46 nM and 72 nM).
    • Cocrystal structures revealed an allosteric binding site between LDHA subunits.
    • Inhibition of LDHA reduced lactate production and glycolysis in MIA PaCa-2 cells.
    • Lead compounds inhibited cancer cell and organoid proliferation, showing synergy with phenformin.
    • Compounds 6 and 21 exhibited favorable pharmacokinetics, including up to 73% oral bioavailability and a half-life > 4 hours in mice.

    Conclusions:

    • Novel succinic acid monoamide derivatives are potent, allosteric inhibitors of LDHA.
    • These compounds effectively reduce pancreatic cancer cell glycolysis and proliferation.
    • The developed inhibitors possess suitable pharmacokinetic profiles, suggesting potential for further development as pancreatic cancer therapeutics.