Anthraquinone derivatives as ADP-competitive inhibitors of liver pyruvate kinase

Amalyn Nain-Perez; Anders Foller Füchtbauer; Liliana Håversen; Aleksei Lulla; Chunxia Gao; Josipa Matic; Leticia Monjas; Alexandra Rodríguez; Paul Brear; Woonghee Kim; Marko Hyvönen; Jan Borén; Adil Mardinoglu; Mathias Uhlen; Morten Grøtli

doi:10.1016/j.ejmech.2022.114270

Anthraquinone derivatives as ADP-competitive inhibitors of liver pyruvate kinase

Amalyn Nain-Perez, Anders Foller Füchtbauer, Liliana Håversen, Aleksei Lulla, Chunxia Gao, Josipa Matic, Leticia Monjas, Alexandra Rodríguez, Paul Brear, Woonghee Kim, Marko Hyvönen, Jan Borén, Adil Mardinoglu, Mathias Uhlen, Morten Grøtli^*

^*Corresponding author for this work

Centre for Host Microbiome Interactions

Research output: Contribution to journal › Article › peer-review

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Abstract

Liver pyruvate kinase (PKL) is a major regulator of metabolic flux and ATP production during liver cell glycolysis and is considered a potential drug target for the treatment of non-alcoholic fatty liver disease (NAFLD). In this study, we report the first ADP-competitive PKL inhibitors and identify several starting points for the further optimization of these inhibitors. Modeling and structural biology guided the optimization of a PKL-specific anthraquinone-based compound. A structure–activity relationship study of 47 novel synthetic derivatives revealed PKL inhibitors with half-maximal inhibitory concentration (IC₅₀) values in the 200 nM range. Despite the difficulty involved in studying a binding site as exposed as the ADP site, these derivatives feature expanded structural diversity and chemical spaces that may be used to improve their inhibitory activities against PKL. The obtained results expand the knowledge of the structural requirements for interactions with the ADP-binding site of PKL.

Original language	English
Article number	114270
Journal	EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
Volume	234
Early online date	12 Mar 2022
DOIs	https://doi.org/10.1016/j.ejmech.2022.114270
Publication status	Published - 15 Apr 2022

Keywords

ADP competitive inhibitors
Enzymatic inhibition
Liver pyruvate kinase
Non-alcoholic fatty liver disease
Structure-activity relationship

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10.1016/j.ejmech.2022.114270

Anthraquinone derivatives as ADP-competitive_NAIN-PEREZ_Published online 8 Mar 22_GOLD VoR (CC BY)Final published version, 2.32 MBLicence: CC BY

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Nain-Perez, A., Foller Füchtbauer, A., Håversen, L., Lulla, A., Gao, C., Matic, J., Monjas, L., Rodríguez, A., Brear, P., Kim, W., Hyvönen, M., Borén, J., Mardinoglu, A., Uhlen, M., & Grøtli, M. (2022). Anthraquinone derivatives as ADP-competitive inhibitors of liver pyruvate kinase. EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY, 234, Article 114270. https://doi.org/10.1016/j.ejmech.2022.114270

@article{b1b635c7b1f4422c93e8ab4434dd2d39,

title = "Anthraquinone derivatives as ADP-competitive inhibitors of liver pyruvate kinase",

abstract = "Liver pyruvate kinase (PKL) is a major regulator of metabolic flux and ATP production during liver cell glycolysis and is considered a potential drug target for the treatment of non-alcoholic fatty liver disease (NAFLD). In this study, we report the first ADP-competitive PKL inhibitors and identify several starting points for the further optimization of these inhibitors. Modeling and structural biology guided the optimization of a PKL-specific anthraquinone-based compound. A structure–activity relationship study of 47 novel synthetic derivatives revealed PKL inhibitors with half-maximal inhibitory concentration (IC50) values in the 200 nM range. Despite the difficulty involved in studying a binding site as exposed as the ADP site, these derivatives feature expanded structural diversity and chemical spaces that may be used to improve their inhibitory activities against PKL. The obtained results expand the knowledge of the structural requirements for interactions with the ADP-binding site of PKL.",

keywords = "ADP competitive inhibitors, Enzymatic inhibition, Liver pyruvate kinase, Non-alcoholic fatty liver disease, Structure-activity relationship",

author = "Amalyn Nain-Perez and {Foller F{\"u}chtbauer}, Anders and Liliana H{\aa}versen and Aleksei Lulla and Chunxia Gao and Josipa Matic and Leticia Monjas and Alexandra Rodr{\'i}guez and Paul Brear and Woonghee Kim and Marko Hyv{\"o}nen and Jan Bor{\'e}n and Adil Mardinoglu and Mathias Uhlen and Morten Gr{\o}tli",

note = "Funding Information: The authors acknowledge financial support from the Knut and Alice Wallenberg Foundation as a Proof-of-Concept grant to JB , and from the Swedish Research Council , the NovoNordisk Foundation and from the Torsten S{\"o}derberg Foundation . We are grateful for the Diamond Light Source for access to beamlines i03, i04, i04-1 and for the data that contributed to these results (proposal mx18548 and mx25402). We thank the X-ray crystallographic facility at the Department of Biochemistry, Cambridge, for access to crystallization instrumentation. Funding Information: The authors acknowledge financial support from the Knut and Alice Wallenberg Foundation as a Proof-of-Concept grant to JB, and from the Swedish Research Council, the NovoNordisk Foundation and from the Torsten S{\"o}derberg Foundation. We are grateful for the Diamond Light Source for access to beamlines i03, i04, i04-1 and for the data that contributed to these results (proposal mx18548 and mx25402). We thank the X-ray crystallographic facility at the Department of Biochemistry, Cambridge, for access to crystallization instrumentation. Publisher Copyright: {\textcopyright} 2022",

year = "2022",

month = apr,

day = "15",

doi = "10.1016/j.ejmech.2022.114270",

language = "English",

volume = "234",

journal = "EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY",

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}

Nain-Perez, A, Foller Füchtbauer, A, Håversen, L, Lulla, A, Gao, C, Matic, J, Monjas, L, Rodríguez, A, Brear, P, Kim, W, Hyvönen, M, Borén, J, Mardinoglu, A, Uhlen, M & Grøtli, M 2022, 'Anthraquinone derivatives as ADP-competitive inhibitors of liver pyruvate kinase', EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY, vol. 234, 114270. https://doi.org/10.1016/j.ejmech.2022.114270

TY - JOUR

T1 - Anthraquinone derivatives as ADP-competitive inhibitors of liver pyruvate kinase

AU - Nain-Perez, Amalyn

AU - Foller Füchtbauer, Anders

AU - Håversen, Liliana

AU - Lulla, Aleksei

AU - Gao, Chunxia

AU - Matic, Josipa

AU - Monjas, Leticia

AU - Rodríguez, Alexandra

AU - Brear, Paul

AU - Kim, Woonghee

AU - Hyvönen, Marko

AU - Borén, Jan

AU - Mardinoglu, Adil

AU - Uhlen, Mathias

AU - Grøtli, Morten

N1 - Funding Information: The authors acknowledge financial support from the Knut and Alice Wallenberg Foundation as a Proof-of-Concept grant to JB , and from the Swedish Research Council , the NovoNordisk Foundation and from the Torsten Söderberg Foundation . We are grateful for the Diamond Light Source for access to beamlines i03, i04, i04-1 and for the data that contributed to these results (proposal mx18548 and mx25402). We thank the X-ray crystallographic facility at the Department of Biochemistry, Cambridge, for access to crystallization instrumentation. Funding Information: The authors acknowledge financial support from the Knut and Alice Wallenberg Foundation as a Proof-of-Concept grant to JB, and from the Swedish Research Council, the NovoNordisk Foundation and from the Torsten Söderberg Foundation. We are grateful for the Diamond Light Source for access to beamlines i03, i04, i04-1 and for the data that contributed to these results (proposal mx18548 and mx25402). We thank the X-ray crystallographic facility at the Department of Biochemistry, Cambridge, for access to crystallization instrumentation. Publisher Copyright: © 2022

PY - 2022/4/15

Y1 - 2022/4/15

N2 - Liver pyruvate kinase (PKL) is a major regulator of metabolic flux and ATP production during liver cell glycolysis and is considered a potential drug target for the treatment of non-alcoholic fatty liver disease (NAFLD). In this study, we report the first ADP-competitive PKL inhibitors and identify several starting points for the further optimization of these inhibitors. Modeling and structural biology guided the optimization of a PKL-specific anthraquinone-based compound. A structure–activity relationship study of 47 novel synthetic derivatives revealed PKL inhibitors with half-maximal inhibitory concentration (IC50) values in the 200 nM range. Despite the difficulty involved in studying a binding site as exposed as the ADP site, these derivatives feature expanded structural diversity and chemical spaces that may be used to improve their inhibitory activities against PKL. The obtained results expand the knowledge of the structural requirements for interactions with the ADP-binding site of PKL.

AB - Liver pyruvate kinase (PKL) is a major regulator of metabolic flux and ATP production during liver cell glycolysis and is considered a potential drug target for the treatment of non-alcoholic fatty liver disease (NAFLD). In this study, we report the first ADP-competitive PKL inhibitors and identify several starting points for the further optimization of these inhibitors. Modeling and structural biology guided the optimization of a PKL-specific anthraquinone-based compound. A structure–activity relationship study of 47 novel synthetic derivatives revealed PKL inhibitors with half-maximal inhibitory concentration (IC50) values in the 200 nM range. Despite the difficulty involved in studying a binding site as exposed as the ADP site, these derivatives feature expanded structural diversity and chemical spaces that may be used to improve their inhibitory activities against PKL. The obtained results expand the knowledge of the structural requirements for interactions with the ADP-binding site of PKL.

KW - ADP competitive inhibitors

KW - Enzymatic inhibition

KW - Liver pyruvate kinase

KW - Non-alcoholic fatty liver disease

KW - Structure-activity relationship

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U2 - 10.1016/j.ejmech.2022.114270

DO - 10.1016/j.ejmech.2022.114270

M3 - Article

AN - SCOPUS:85126082961

SN - 0223-5234

VL - 234

JO - EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY

JF - EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY

M1 - 114270

ER -

Anthraquinone derivatives as ADP-competitive inhibitors of liver pyruvate kinase

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