Exploring positions 6 and 7 of a quinazoline-based scaffold leads to changes in selectivity and potency towards RIPK2/3 kinases

0574898 - ÚOCHB 2024 RIV NL eng J - Článek v odborném periodiku
Misehe, Mbilo - Matoušová, Marika - Dvořáková, Alexandra - Hercík, Kamil - Škach, Kryštof - Chalupská, Dominika - Dejmek, Milan - Šála, Michal - Hájek, Miroslav - Bouřa, Evžen - Mertlíková-Kaiserová, Helena - Nencka, Radim
Exploring positions 6 and 7 of a quinazoline-based scaffold leads to changes in selectivity and potency towards RIPK2/3 kinases.
European Journal of Medicinal Chemistry. Roč. 260, November (2023), č. článku 115717. ISSN 0223-5234. E-ISSN 1768-3254
Grant CEP: GA MŠMT(CZ) LX22NPO5103; GA MZd(CZ) NU20-05-00472
Institucionální podpora: RVO:61388963
Klíčová slova: kinase inhibitor * quinazoline derivatives * RIPK2 * NOD * inflammation * RIPK3
Obor OECD: Medicinal chemistry
Impakt faktor: 6.7, rok: 2022
Způsob publikování: Open access
https://doi.org/10.1016/j.ejmech.2023.115717

Receptor-interacting protein kinases 2 and 3 (RIPK2 and RIPK3) are considered attractive therapeutic enzyme targets for the treatment of a multitude of inflammatory diseases and cancers. In this study, we developed three interrelated series of novel quinazoline-based derivatives to investigate the effects of extensive modifications of positions 6 and 7 of the central core on the inhibitory activity and the selectivity against these RIPKs. The design of the derivatives was inspired by analyses of available literary knowledge on both RIPK2 and RIPK3 in complex with known quinazoline or quinoline inhibitors. Enzymatic investigations for bioactivity of the prepared molecules against purified RIPKs (RIPK1-4) shed light on multiple potent and selective RIPK2 and dual RIPK2/3 inhibitors. Furthermore, evaluations in living cells against the RIPK2-NOD1/2-mediated signaling pathways, identified as the potential primary targets, demonstrated nanomolar inhibition for a majority of the compounds. In addition, we have demonstrated overall good stability of various lead inhibitors in both human and mouse microsomes and plasma. Several of these compounds also were evaluated for selectivity across 58 human kinases other than RIPKs, exhibiting outstanding specificity profiles. We have thus clearly demonstrated that tuning appropriate substitutions at positions 6 and 7 of the developed quinazoline derivatives may lead to interesting potency and specificities against RIPK2 and RIPK3. This knowledge might therefore be employed for the targeted preparation of new, highly potent and selective tools against these RIPKs, which could be of utility in biological and clinical research.
Trvalý link: https://hdl.handle.net/11104/0344824