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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

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