IPP/CNRS-A017: A chemical probe for human dihydroorotate dehydrogenase (hDHODH)

Andreas Krämer (1, 2, 3) , Amelie Tjaden (1, 2) , Benardina Ndreshkjana (4, 3) , Claudia Tredup (1, 2) , Henner Farin (4, 5, 3) , Stefan Knapp (6, 1, 2) , Yves Janin (7) , Susanne Müller (1, 2)

1 Johann Wolfgang Goethe University
2 Buchmann Institute for Molecular Life Sciences and Structural Genomics Consortium (SGC)
3 Goethe University Frankfurt
4 Institute for Tumor Biology and Experimental Therapy [Frankfurt, Germany]
5 DKTK - German Cancer Consortium [Heidelberg]
6 Goethe-Universität Frankfurt am Main
7 STRING - Structure et Instabilité des Génomes

Human Dihydroorotate dehydrogenase, which catalyses de novo pyrimidine biosynthesis, is an emerging target for treatment of infectious diseases, arthritis and cancer. In order to provide a chemical tool studying this key enzyme, we characterized IPP/CNRS-A017, a highly potent, selective, and cell-active inhibitor of the human Dihydroorotate dehydrogenase (hDHODH). In this report, we describe the crystal structure of IPP/CNRS-A017 in complex with hDHODH, providing inside into its binding mode. Additionally, further off-target profiling in a kinome-wide screen and a G-Protein-Coupled Receptors screen as well as investigated cell viability effects in three different cell lines (HEK293T, U2OS, human fibroblasts) confirmed that IPP/CNRS-A017 is a highly selective chemical tool to study the biology of hDHODH. Specific sensitivity to IPP/CNRS-A017 was observed in patient-derived colorectal cancer organoids.

Mots clés: hDHODH; Crystal structure; Chemical probe; Organoids; Viability assessment

Domaines: Chimie organique

Andreas Krämer, Amelie Tjaden, Benardina Ndreshkjana, Claudia Tredup, Henner Farin, et al.. IPP/CNRS-A017: A chemical probe for human dihydroorotate dehydrogenase (hDHODH). Current Research in Chemical Biology, 2022, 2, pp.100034. ⟨10.1016/j.crchbi.2022.100034⟩. ⟨hal-03769456⟩