Back to Search
Start Over
Synthesis and biological characterization of an orally bioavailable lactate dehydrogenase-A inhibitor against pancreatic cancer.
- Source :
-
European journal of medicinal chemistry [Eur J Med Chem] 2024 Sep 05; Vol. 275, pp. 116598. Date of Electronic Publication: 2024 Jun 17. - Publication Year :
- 2024
-
Abstract
- Lactate dehydrogenase-A (LDHA) is the major isoform of lactate dehydrogenases (LDH) that is overexpressed and linked to poor survival in pancreatic ductal adenocarcinoma (PDAC). Despite some progress, current LDH inhibitors have poor structural and physicochemical properties or exhibit unfavorable pharmacokinetics that have hampered their development. The present study reports the synthesis and biological evaluation of a novel class of LDHA inhibitors comprising a succinic acid monoamide motif. Compounds 6 and 21 are structurally related analogs that demonstrated potent inhibition of LDHA with IC <subscript>50</subscript> s of 46 nM and 72 nM, respectively. We solved cocrystal structures of compound 21-bound to LDHA that showed that the compound binds to a distinct allosteric site between the two subunits of the LDHA tetramer. Inhibition of LDHA correlated with reduced lactate production and reduction of glycolysis in MIA PaCa-2 pancreatic cancer cells. The lead compounds inhibit the proliferation of human pancreatic cancer cell lines and patient-derived 3D organoids and exhibit a synergistic cytotoxic effect with the OXPHOS inhibitor phenformin. Unlike current LDHA inhibitors, 6 and 21 have appropriate pharmacokinetics and ligand efficiency metrics, exhibit up to 73% oral bioavailability, and a cumulative half-life greater than 4 h in mice.<br />Competing Interests: Declaration of competing interest On behalf of all the authors, the corresponding author declares that there is no known financial interests or personal relationships that that could inappropriately influence (bias) the work reported in the manuscript.<br /> (Copyright © 2024 The Author(s). Published by Elsevier Masson SAS.. All rights reserved.)
- Subjects :
- Humans
Animals
Administration, Oral
Mice
Structure-Activity Relationship
Molecular Structure
Drug Screening Assays, Antitumor
Biological Availability
Dose-Response Relationship, Drug
L-Lactate Dehydrogenase antagonists & inhibitors
L-Lactate Dehydrogenase metabolism
Cell Line, Tumor
Models, Molecular
Pancreatic Neoplasms drug therapy
Pancreatic Neoplasms pathology
Antineoplastic Agents pharmacology
Antineoplastic Agents chemical synthesis
Antineoplastic Agents chemistry
Enzyme Inhibitors pharmacology
Enzyme Inhibitors chemical synthesis
Enzyme Inhibitors chemistry
Cell Proliferation drug effects
Subjects
Details
- Language :
- English
- ISSN :
- 1768-3254
- Volume :
- 275
- Database :
- MEDLINE
- Journal :
- European journal of medicinal chemistry
- Publication Type :
- Academic Journal
- Accession number :
- 38925013
- Full Text :
- https://doi.org/10.1016/j.ejmech.2024.116598