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doi:10.22028/D291-44270
Titel: | Discovery of a novel, selective CK2 inhibitor class with an unusual basic scaffold |
VerfasserIn: | Khalifa, Hend ElHady, Ahmed K. Liu, Ting Elgaher, Walid A. M. Filhol-Cochet, Odile Cochet, Claude Abadi, Ashraf H. Hamed, Mostafa M. Abdel-Halim, Mohammad Engel, Matthias |
Sprache: | Englisch |
Titel: | European Journal of Medicinal Chemistry |
Bandnummer: | 282 (2025) |
Verlag/Plattform: | Elsevier |
Erscheinungsjahr: | 2024 |
Freie Schlagwörter: | ATP-Competitive inhibition Kinase inhibitors CK2 Thienopyrimidines |
DDC-Sachgruppe: | 500 Naturwissenschaften |
Dokumenttyp: | Journalartikel / Zeitschriftenartikel |
Abstract: | CK2 is a Ser/Thr-protein kinase playing a crucial role in promoting cell growth and survival, hence it is considered a promising target for anti-cancer drugs. However, many previously reported CK2 inhibitors lack selectivity. In search of novel scaffolds for selective CK2 inhibition, we identified a dihydropyrido-thieno[2,3-d] pyrimidine derivative displaying submicromolar inhibitory activity against CK2α. This scaffold captured our interest because of the basic secondary amine, a rather unusual motif for CK2 inhibitors. Our optimization strategy comprised the incorporation of a 4-piperazinyl moiety as a linker group and introduction of varying substituents on the pendant phenyl ring. All resulting compounds exhibited potent CK2α inhibition, with IC50 values in the nanomolar range. Compound 10b demonstrated the most balanced activity profile with a cell-free IC50 value of 36.7 nM and a notable cellular activity with a GI50 of 7.3 μM and 7.5 μM against 786-O renal cell carcinoma and U937 lymphoma cells, respectively. 10b displayed excellent selectivity when screened against a challenging kinase selectivity profiling panel. Moreover, 10b inhibited CK2 in the cells, albeit less potently than CX-4945, but induced cell death more strongly than CX-4945. Altogether, we have identified a novel CK2 inhibitory scaffold with drug-like physicochemical properties in a favorable basic pKa range. |
DOI der Erstveröffentlichung: | 10.1016/j.ejmech.2024.117048 |
URL der Erstveröffentlichung: | https://doi.org/10.1016/j.ejmech.2024.117048 |
Link zu diesem Datensatz: | urn:nbn:de:bsz:291--ds-442705 hdl:20.500.11880/39566 http://dx.doi.org/10.22028/D291-44270 |
ISSN: | 0223-5234 |
Datum des Eintrags: | 4-Feb-2025 |
Bezeichnung des in Beziehung stehenden Objekts: | Supplementary data |
In Beziehung stehendes Objekt: | https://ars.els-cdn.com/content/image/1-s2.0-S0223523424009309-mmc1.pdf |
Fakultät: | NT - Naturwissenschaftlich- Technische Fakultät |
Fachrichtung: | NT - Pharmazie |
Professur: | NT - Prof. Dr. Christian Ducho |
Sammlung: | SciDok - Der Wissenschaftsserver der Universität des Saarlandes |
Dateien zu diesem Datensatz:
Datei | Beschreibung | Größe | Format | |
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1-s2.0-S0223523424009309-main.pdf | 5,56 MB | Adobe PDF | Öffnen/Anzeigen |
Diese Ressource wurde unter folgender Copyright-Bestimmung veröffentlicht: Lizenz von Creative Commons