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Titel: Discovery and anticancer screening of novel oxindole-based derivative bearing pyridyl group as potent and selective dual FLT3/CDK2 kinase inhibitor
Autor(en): Soudi, Aya
Bender, Onur
Celik, Ismail
El-Hafeez, Amer Ali Abd
Dogan, Rumeysa
Atalay, Arzu
Elkaeed, Eslam B.
Alsfouk, Aisha A.
Abdelhafez, Elshimaa M.In der Gemeinsamen Normdatei der DNB nachschlagen
Aly, Omar M.
Sippl, WolfgangIn der Gemeinsamen Normdatei der DNB nachschlagen
Ali, Taha F. S.
Erscheinungsdatum: 2024
Art: Artikel
Sprache: Englisch
Zusammenfassung: Protein kinases regulate cellular activities and make up over 60% of oncoproteins and proto-oncoproteins. Among these kinases, FLT3 is a member of class III receptor tyrosine kinase family which is abundantly expressed in individuals with acute leukemia. Our previous oxindole-based hit has a particular affinity toward FLT3 (IC50 = 2.49 μM) and has demonstrated selectivity towards FLT3 ITD-mutated MV4-11 AML cells, with an IC50 of 4.3 μM. By utilizing the scaffold of the previous hit, sixteen new compounds were synthesized and screened against NCI-60 human cancer cell lines. This leads to the discovery of a potent antiproliferative compound, namely 5l, with an average GI50 value against leukemia and colon cancer subpanels equalling 3.39 and 5.97 µM, respectively. Screening against a specific set of 10 kinases that are associated with carcinogenesis indicates that compound 5l has a potent FLT3 inhibition (IC50 = 36.21 ± 1.07 nM). Remarkably, compound 5l was three times more effective as a CDK2 inhibitor (IC50 = 8.17 ± 0.32 nM) compared to sunitinib (IC50 = 27.90 ± 1.80 nM). Compound 5l was further analyzed by means of docking and molecular dynamics simulation for CDK2 and FLT3 active sites which provided a rational for the observed strong inhibition of kinases. These results suggest a novel structural scaffold candidate that simultaneously inhibits CDK2 and FLT3 and gives encouragement for further development as a potential therapeutic for leukemia and colon cancer.
URI: https://opendata.uni-halle.de//handle/1981185920/118452
http://dx.doi.org/10.25673/116497
Open-Access: Open-Access-Publikation
Nutzungslizenz: (CC BY 4.0) Creative Commons Namensnennung 4.0 International(CC BY 4.0) Creative Commons Namensnennung 4.0 International
Journal Titel: Pharmaceuticals
Verlag: MDPI
Verlagsort: Basel
Band: 17
Heft: 5
Originalveröffentlichung: 10.3390/ph17050659
Enthalten in den Sammlungen:Open Access Publikationen der MLU

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