Discovery of novel human lactate dehydrogenase inhibitors: Structure-based virtual screening studies and biological assessment

Laura Di Magno; Antonio Coluccia; Marianna Bufano; Silvia Ripa; Giuseppe La Regina; Marianna Nalli; Fiorella Di Pastena; Gianluca Canettieri; Romano Silvestri; Luigi Frati

doi:10.1016/j.ejmech.2022.114605

Discovery of novel human lactate dehydrogenase inhibitors: Structure-based virtual screening studies and biological assessment

Eur J Med Chem. 2022 Oct 5:240:114605. doi: 10.1016/j.ejmech.2022.114605. Epub 2022 Jul 14.

Authors

Affiliations

¹ Laboratory Affiliated with the Institute Pasteur Italy - Cenci Bolognetti Foundation, Department of Molecular Medicine, Sapienza University of Rome, Viale Regina Elena 291, I-00161, Rome, Italy. Electronic address: laura.dimagno@uniroma1.it.
² Laboratory Affiliated with the Institute Pasteur Italy - Cenci Bolognetti Foundation, Department of Drug Chemistry and Technologies, Sapienza University of Rome, Piazzale Aldo Moro 5, I-00185, Rome, Italy. Electronic address: antonio.coluccia@uniroma.it.
³ Laboratory Affiliated with the Institute Pasteur Italy - Cenci Bolognetti Foundation, Department of Drug Chemistry and Technologies, Sapienza University of Rome, Piazzale Aldo Moro 5, I-00185, Rome, Italy.
⁴ Laboratory Affiliated with the Institute Pasteur Italy - Cenci Bolognetti Foundation, Department of Molecular Medicine, Sapienza University of Rome, Viale Regina Elena 291, I-00161, Rome, Italy.
⁵ Laboratory Affiliated with the Institute Pasteur Italy - Cenci Bolognetti Foundation, Department of Molecular Medicine, Sapienza University of Rome, Viale Regina Elena 291, I-00161, Rome, Italy. Electronic address: gianluca.canettieri@uniroma1.it.
⁶ Laboratory Affiliated with the Institute Pasteur Italy - Cenci Bolognetti Foundation, Department of Drug Chemistry and Technologies, Sapienza University of Rome, Piazzale Aldo Moro 5, I-00185, Rome, Italy. Electronic address: romano.silvestri@uniroma1.it.
⁷ Institute Pasteur Italy - Cenci Bolognetti Foundation, Via Regina Elena 291, I-00161, Rome, Italy; IRCCS Neuromed S.p.A., Via Atinense 18, Pozzilli, Isernia, Italy. Electronic address: direzione.scientifica@neuromed.it.

PMID: 35868126
DOI: 10.1016/j.ejmech.2022.114605

Abstract

Most cancer cells switch their metabolism from mitochondrial oxidative phosphorylation to aerobic glycolysis to generate ATP and precursors for the biosynthesis of key macromolecules. The aerobic conversion of pyruvate to lactate, coupled to oxidation of the nicotinamide cofactor, is a primary hallmark of cancer and is catalyzed by lactate dehydrogenase (LDH), a central effector of this pathological reprogrammed metabolism. Hence, inhibition of LDH is a potential new promising therapeutic approach for cancer. In the search for new LDH inhibitors, we carried out a structure-based virtual screening campaign. Here, we report the identification of a novel specific LDH inhibitor, the pyridazine derivative 18 (RS6212), that exhibits potent anticancer activity within the micromolar range in multiple cancer cell lines and synergizes with complex I inhibition in the suppression of tumor growth. Altogether, our data support the conclusion that compound 18 deserves to be further investigated as a starting point for the development of LDH inhibitors and for novel anticancer strategies based on the targeting of key metabolic steps.

Keywords: Cancer; Glycolysis; Inhibition; Lactate dehydrogenase; Virtual screening.

MeSH terms

Cell Line
Enzyme Inhibitors / pharmacology
Glycolysis
Humans
L-Lactate Dehydrogenase* / metabolism
Lactic Acid
Neoplasms* / drug therapy
Neoplasms* / pathology
Oxidative Phosphorylation

Substances

Enzyme Inhibitors
Lactic Acid
L-Lactate Dehydrogenase