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

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.
Laura Di Magno 1,  Antonio Coluccia 2,  Marianna Bufano 3,  Silvia Ripa 4,  Giuseppe La Regina 3,  Marianna Nalli 3,  Fiorella Di Pastena 4,  Gianluca Canettieri 5,  Romano Silvestri 6,  Luigi Frati 7
Affiliations

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: [email protected].
  • 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: [email protected].
  • 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: [email protected].
  • 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: [email protected].
  • 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: [email protected].
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.

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