Počet záznamů: 1
Exploring positions 6 and 7 of a quinazoline-based scaffold leads to changes in selectivity and potency towards RIPK2/3 kinases
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SYSNO ASEP 0574898 Druh ASEP J - Článek v odborném periodiku Zařazení RIV J - Článek v odborném periodiku Poddruh J Článek ve WOS Název Exploring positions 6 and 7 of a quinazoline-based scaffold leads to changes in selectivity and potency towards RIPK2/3 kinases Tvůrce(i) Misehe, Mbilo (UOCHB-X)
Matoušová, Marika (UOCHB-X) ORCID
Dvořáková, Alexandra (UOCHB-X)
Hercík, Kamil (UOCHB-X)
Škach, Kryštof (UOCHB-X)
Chalupská, Dominika (UOCHB-X) ORCID
Dejmek, Milan (UOCHB-X) RID, ORCID
Šála, Michal (UOCHB-X) RID, ORCID
Hájek, Miroslav (UOCHB-X) RID, ORCID
Bouřa, Evžen (UOCHB-X) ORCID
Mertlíková-Kaiserová, Helena (UOCHB-X) RID, ORCID
Nencka, Radim (UOCHB-X) RID, ORCIDČíslo článku 115717 Zdroj.dok. European Journal of Medicinal Chemistry. - : Elsevier - ISSN 0223-5234
Roč. 260, November (2023)Poč.str. 19 s. Jazyk dok. eng - angličtina Země vyd. NL - Nizozemsko Klíč. slova kinase inhibitor ; quinazoline derivatives ; RIPK2 ; NOD ; inflammation ; RIPK3 Obor OECD Medicinal chemistry CEP LX22NPO5103 GA MŠMT - Ministerstvo školství, mládeže a tělovýchovy NU20-05-00472 GA MZd - Ministerstvo zdravotnictví Způsob publikování Open access Institucionální podpora UOCHB-X - RVO:61388963 UT WOS 001068947900001 EID SCOPUS 85168146955 DOI 10.1016/j.ejmech.2023.115717 Anotace 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. Pracoviště Ústav organické chemie a biochemie Kontakt asep@uochb.cas.cz ; Kateřina Šperková, Tel.: 232 002 584 ; Jana Procházková, Tel.: 220 183 418 Rok sběru 2024 Elektronická adresa https://doi.org/10.1016/j.ejmech.2023.115717
Počet záznamů: 1