Author: Borén, Jan ; Brear, Paul ; Nilsson, Oscar ; Håversen, Liliana ; Hyvönen, Marko ; Nain-Perez, Amalyn ; Liljenberg, Sara ; Grøtli, Morten ; Lulla, Aleksei

The liver isoform of pyruvate kinase (PKL) has gained interest due to its potential capacity to regulate fatty acid synthesis involved in the progression of non-alcoholic fatty liver disease (NAFLD). Here we describe a novel series of PKL modulators that can either activate or inhibit the enzyme allosterically, from a cryptic site at the interface of two protomers in the tetrameric enzyme. Starting from urolithin D, we designed and synthesised 42 new compounds. The effect of these compounds on PKL enzymatic activity was assessed after incubation with cell lysates obtained from a liver cell line. Pronounced activation of PKL activity, up to 3.8-fold, was observed for several compounds at 10 μM, while other compounds were prominent PKL inhibitors reducing its activity to 81% at best. A structure-activity relationship identified linear-shaped sulfone-sulfonamides as activators and non-linear compounds as inhibitors. Crystal structures revealed the conformations of these modulators, which were used as a reference for designing new modulators.

01 Apr 2022·European Journal of Medicinal ChemistryQ1 · MEDICINE

Anthraquinone derivatives as ADP-competitive inhibitors of liver pyruvate kinase

Q1 · MEDICINE

Article

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

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.

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Indication	Highest Phase	Country/Location	Organization	Date
Nonalcoholic Steatohepatitis	Preclinical	-	University of Gothenburg	01 Feb 2023

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