Researchers led by Radim Nencka from IOCB Prague in collaboration with Helena Mertlíková-Kaiserová and Evžen Bouřa synthesized and tested new potent and selective inhibitors for receptor-interacting protein kinases 2 and 3 (RIPK2, RIPK3), which are attractive targets for the treatment of inflammatory diseases and cancer.
Inspired by RIPK inhibitors available in the literature, the researchers developed the new ones by extensive modifications of positions 6 and 7 of a quinazoline-based scaffold. Several lead compounds exerted nanomolar inhibition in enzymatic assays and expressed good metabolic stability in both human and mouse microsomes and plasma. In cellular assays, the lead compounds exerted low nanomolar inhibition of the RIPK2-mediated NOD1/2 pro-inflammatory pathways.
Read the paper: Misehe, M.; Matoušová, M.; Dvořáková, A.; Hercík, K.; Škach, K.; Chalupská, D.; Dejmek, M.; Šála, M.; Hájek, M.; Bouřa, E.; Mertlíková-Kaiserová, H.; Nencka, R. Exploring positions 6 and 7 of a quinazoline-based scaffold leads to changes in selectivity and potency towards RIPK2/3 kinases. Eur. J. Med. Chem. 2023, 260, 15, 115717. https://doi.org/10.1016/j.ejmech.2023.115717
