IPP/CNRS-A017: A chemical probe for human dihydroorotate dehydrogenase (hDHODH) - Archive ouverte HAL Access content directly
Journal Articles Current Research in Chemical Biology Year : 2022

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

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Yves Janin

Abstract

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.
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Dates and versions

hal-03769456 , version 1 (07-10-2022)

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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⟩
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