1. Synthesis and biological characterization of an orally bioavailable lactate dehydrogenase-A inhibitor against pancreatic cancer.
- Author
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Sharma H, Mondal S, Urquiza U, Esparza C, Bartlett S, Santa-Pinter L, Hill H, White M, Sharma P, Luckett-Chastain L, Cooper A, Rasel M, Gao P, Battaile KP, Shukla SK, Lovell S, and Ihnat MA
- 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
- 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
50 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., 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., (Copyright © 2024 The Author(s). Published by Elsevier Masson SAS.. All rights reserved.)- Published
- 2024
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