Sulfone-based human liver pyruvate kinase inhibitors - Design, synthesis and in vitro bioactivity.

Autor: Matić J; Department of Chemistry and Molecular Biology, University of Gothenburg, SE-412 96, Gothenburg, Sweden; Science for Life Laboratory, KTH - Royal Institute of Technology, Stockholm, Sweden., Akladios F; Department of Chemistry and Molecular Biology, University of Gothenburg, SE-412 96, Gothenburg, Sweden; Science for Life Laboratory, KTH - Royal Institute of Technology, Stockholm, Sweden., Battisti UM; Department of Chemistry and Molecular Biology, University of Gothenburg, SE-412 96, Gothenburg, Sweden; Science for Life Laboratory, KTH - Royal Institute of Technology, Stockholm, Sweden., Håversen L; Department of Molecular and Clinical Medicine, University of Gothenburg and Sahlgrenska University Hospital, SE-413 45, Gothenburg, Sweden., Nain-Perez A; Department of Chemistry and Molecular Biology, University of Gothenburg, SE-412 96, Gothenburg, Sweden; Science for Life Laboratory, KTH - Royal Institute of Technology, Stockholm, Sweden., Füchtbauer AF; Department of Chemistry and Molecular Biology, University of Gothenburg, SE-412 96, Gothenburg, Sweden; Science for Life Laboratory, KTH - Royal Institute of Technology, Stockholm, Sweden., Kim W; Science for Life Laboratory, KTH - Royal Institute of Technology, Stockholm, Sweden., Monjas L; Department of Chemistry and Molecular Biology, University of Gothenburg, SE-412 96, Gothenburg, Sweden; Science for Life Laboratory, KTH - Royal Institute of Technology, Stockholm, Sweden., Rivero AR; Department of Chemistry and Molecular Biology, University of Gothenburg, SE-412 96, Gothenburg, Sweden; Science for Life Laboratory, KTH - Royal Institute of Technology, Stockholm, Sweden., Borén J; Department of Molecular and Clinical Medicine, University of Gothenburg and Sahlgrenska University Hospital, SE-413 45, Gothenburg, Sweden., Mardinoglu A; Science for Life Laboratory, KTH - Royal Institute of Technology, Stockholm, Sweden; Centre for Host-Microbiome Interactions, Faculty of Dentistry, Oral & Craniofacial Sciences, King's College London, London, SE1 9RT, UK., Uhlen M; Science for Life Laboratory, KTH - Royal Institute of Technology, Stockholm, Sweden., Grøtli M; Department of Chemistry and Molecular Biology, University of Gothenburg, SE-412 96, Gothenburg, Sweden. Electronic address: grotli@gu.se.
Jazyk: angličtina
Zdroj: European journal of medicinal chemistry [Eur J Med Chem] 2024 Apr 05; Vol. 269, pp. 116306. Date of Electronic Publication: 2024 Mar 05.
DOI: 10.1016/j.ejmech.2024.116306
Abstrakt: Non-alcoholic fatty liver disease (NAFLD) is a prevalent pathological condition characterised by the accumulation of fat in the liver. Almost one-third of the global population is affected by NAFLD, making it a significant health concern. However, despite its prevalence, there is currently no approved drug specifically designed for the treatment of NAFLD. To address this critical gap, researchers have been investigating potential targets for NAFLD drug development. One promising candidate is the liver isoform of pyruvate kinase (PKL). In recent studies, Urolithin C, an allosteric inhibitor of PKL, has emerged as a potential lead compound for therapeutic intervention. Building upon this knowledge, our team has conducted a comprehensive structure-activity relationship of Urolithin C. In this work, we have employed a scaffold-hopping approach, modifying the urolithin structure by replacing the urolithin carbonyl with a sulfone moiety. Our structure-activity relationship analysis has identified the sulfone group as particularly favourable for potent PKL inhibition. Additionally, we have found that the presence of catechol moieties on the two aromatic rings further improves the inhibitory activity. The most promising inhibitor from this new series displayed nanomolar inhibition, boasting an IC 50 value of 0.07 μM. This level of potency rivals that of urolithin D and significantly surpasses the effectiveness of urolithin C by an order of magnitude. To better understand the molecular interactions underlying this inhibition, we obtained the crystal structure of one of the inhibitors complexed with PKL. This structural insight served as a valuable reference point, aiding us in the design of inhibitors.
Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Adil Mardinoglu reports financial support was provided by ScandiEdge Therapeutics AB. Jan Boren reports financial support was provided by Knut and Alice Wallenberg Foundation. Jan Boren reports financial support was provided by Swedish Research Council. Adil Mardinoglu reports was provided by Ogonoris Foundation. Jan Boren reports was provided by Torsten Söderberg Foundation.
(Copyright © 2024 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)
Databáze: MEDLINE
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