Inhibitors of Fumarylacetoacetate Hydrolase Domain Containing Protein 1 (FAHD1)
Alexander K. H. Weiss,
Richard Wurzer,
Patrycia Klapec,
Manuel Philip Eder,
Johannes R. Loeffler,
Susanne von Grafenstein,
Stefania Monteleone,
Klaus R. Liedl,
Pidder Jansen-Dürr,
Hubert Gstach
Affiliations
Alexander K. H. Weiss
Research Institute for Biomedical Aging Research, University of Innsbruck, Rennweg 10, A-6020 Innsbruck, Austria
Richard Wurzer
Department of Organic Chemistry, Faculty of Chemistry, University of Vienna, Währinger Straße 38, A-1090 Vienna, Austria
Patrycia Klapec
Campus Tulln, University of Applied Sciences Wiener Neustadt, Konrad-Lorenz-Straße 10, A-3430 Tulln an der Donau, Austria
Manuel Philip Eder
Campus Tulln, University of Applied Sciences Wiener Neustadt, Konrad-Lorenz-Straße 10, A-3430 Tulln an der Donau, Austria
Johannes R. Loeffler
Institute of General, Inorganic and Theoretical Chemistry, University of Innsbruck, Innrain 58, A-6020 Innsbruck, Austria
Susanne von Grafenstein
Institute of General, Inorganic and Theoretical Chemistry, University of Innsbruck, Innrain 58, A-6020 Innsbruck, Austria
Stefania Monteleone
Institute of General, Inorganic and Theoretical Chemistry, University of Innsbruck, Innrain 58, A-6020 Innsbruck, Austria
Klaus R. Liedl
Institute of General, Inorganic and Theoretical Chemistry, University of Innsbruck, Innrain 58, A-6020 Innsbruck, Austria
Pidder Jansen-Dürr
Research Institute for Biomedical Aging Research, University of Innsbruck, Rennweg 10, A-6020 Innsbruck, Austria
Hubert Gstach
Department of Pharmaceutical Sciences, Pharmaceutical Chemistry Division, Faculty of Life Sciences, University of Vienna, Althanstraße 14, UZ2 E349, A-1090 Vienna, Austria
FAH domain containing protein 1 (FAHD1) acts as oxaloacetate decarboxylase in mitochondria, contributing to the regulation of the tricarboxylic acid cycle. Guided by a high-resolution X-ray structure of FAHD1 liganded by oxalate, the enzymatic mechanism of substrate processing is analyzed in detail. Taking the chemical features of the FAHD1 substrate oxaloacetate into account, the potential inhibitor structures are deduced. The synthesis of drug-like scaffolds afforded first-generation FAHD1-inhibitors with activities in the low micromolar IC50 range. The investigations disclosed structures competing with the substrate for binding to the metal cofactor, as well as scaffolds, which may have a novel binding mode to FAHD1.
