Cofactor mimicry is a popular strategy for the development of enzyme inhibitors, however, this approach can lead to off-target effects due to the evolutionary conservation of, e.g. purine binding sites across the proteome. In a new study just published in the Journal of Medicinal Chemistry led by Esra Balikci, Anne-Sophie Marques and Ludwig Bauer from the Kilian Huber lab, CMD scientists show that the FDA-approved BTK inhibitor ibrutinib interacts with two unknown target proteins via non-covalent interactions. Surprisingly, the team could demonstrate this mechanism does not involve the canonical reactive acrylamide warhead commonly found in BTK inhibitors. The two newly identified off-targets are proteins thought to be involved in ADP-ribose metabolism. Notably, whereas NUDT5 has itself been suggested as an attractive target for antitumour therapy, the cellular functions of NUDT14 remain largely unexplored. Therefore, these new results pave the way for the development of novel tool compounds for NUDT5 and NUDT14 but also raise important questions about covalent inhibitor development and pharmacology.
Read the full story here: https://pubs.acs.org/doi/10.1021/acs.jmedchem.4c00072