Design, synthesis, biological evaluation, and docking studies of novel (imidazol-5-yl)pyrimidine-based derivatives as dual BRAFV600E/p38α inhibitors
DC Field | Value | Language |
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dc.contributor.author | Ali, E.M.H. | - |
dc.contributor.author | El-Telbany, R.F.A. | - |
dc.contributor.author | Abdel-Maksoud, M.S. | - |
dc.contributor.author | Ammar, U.M. | - |
dc.contributor.author | Mersal, K.I. | - |
dc.contributor.author | Zaraei, S.-O. | - |
dc.contributor.author | El-Gamal, M.I. | - |
dc.contributor.author | Choi, S.-I. | - |
dc.contributor.author | Lee, K.-T. | - |
dc.contributor.author | Kim, H.-K. | - |
dc.contributor.author | Lee, K.H. | - |
dc.contributor.author | Oh, C.-H. | - |
dc.date.accessioned | 2021-12-02T20:41:49Z | - |
dc.date.available | 2021-12-02T20:41:49Z | - |
dc.date.created | 2021-08-31 | - |
dc.date.issued | 2021-04-05 | - |
dc.identifier.issn | 0223-5234 | - |
dc.identifier.uri | https://scholar.korea.ac.kr/handle/2021.sw.korea/128961 | - |
dc.description.abstract | The synergistic effect of dual inhibition of serine/threonine protein kinases that are involved in the same signalling pathway of the diseases can exert superior biological benefits for treatment of these diseases. In the present work, a new series of (imidazol-5-yl)pyrimidine was designed and synthesized as dual inhibitors of BRAFV600E and p38α kinases which are considered as key regulators in mitogen-activated protein kinase (MAPK) signalling pathway. The target compounds were evaluated for dual kinase inhibitory activity. The tested compounds exhibited nanomolar scale IC50 values against BRAFV600E and low to sub-micromolar IC50 range against p38α. Compound 20h was identified as the most potent dual BRAFV600E/p38α inhibitor with IC50 values of 2.49 and 85 nM, respectively. Further deep investigation revealed that compound 20h possesses inhibitory activity of TNF-α production in lipopolysaccharide-induced RAW 264.7 macrophages with IC50 value of 96.3 nM. Additionally, the target compounds efficiently frustrated the proliferation of LOX-IMVI melanoma cell line. Compound 20h showed a satisfactory antiproliferative activity with IC50 value of 13 μM, while, compound 18f exhibited the highest cytotoxicity potency with IC50 value of 0.9 μM. Compound 18f is 11.11-fold more selective toward LOX-IMVI melanoma cells than IOSE-80PC normal cells. The newly reported compounds represent therapeutically promising candidates for further development of BRAFV600E/p38α inhibitors in an attempt to overcome the acquired resistance of BRAF mutant melanoma. © 2021 Elsevier Masson SAS | - |
dc.language | English | - |
dc.language.iso | en | - |
dc.publisher | Elsevier Masson s.r.l. | - |
dc.title | Design, synthesis, biological evaluation, and docking studies of novel (imidazol-5-yl)pyrimidine-based derivatives as dual BRAFV600E/p38α inhibitors | - |
dc.type | Article | - |
dc.contributor.affiliatedAuthor | Lee, K.H. | - |
dc.identifier.doi | 10.1016/j.ejmech.2021.113277 | - |
dc.identifier.scopusid | 2-s2.0-85100968552 | - |
dc.identifier.wosid | 000634820600024 | - |
dc.identifier.bibliographicCitation | European Journal of Medicinal Chemistry, v.215 | - |
dc.relation.isPartOf | European Journal of Medicinal Chemistry | - |
dc.citation.title | European Journal of Medicinal Chemistry | - |
dc.citation.volume | 215 | - |
dc.type.rims | ART | - |
dc.type.docType | Article | - |
dc.description.journalClass | 1 | - |
dc.description.journalRegisteredClass | scie | - |
dc.description.journalRegisteredClass | scopus | - |
dc.relation.journalResearchArea | Pharmacology & Pharmacy | - |
dc.relation.journalWebOfScienceCategory | Chemistry, Medicinal | - |
dc.subject.keywordPlus | ACTIVATED PROTEIN-KINASES | - |
dc.subject.keywordPlus | METASTATIC MELANOMA | - |
dc.subject.keywordPlus | RAF INHIBITORS | - |
dc.subject.keywordPlus | PATHWAY | - |
dc.subject.keywordPlus | BRAF | - |
dc.subject.keywordPlus | ERK | - |
dc.subject.keywordPlus | RESISTANCE | - |
dc.subject.keywordPlus | MUTATIONS | - |
dc.subject.keywordPlus | CELLS | - |
dc.subject.keywordPlus | DABRAFENIB | - |
dc.subject.keywordAuthor | BRAFV600E | - |
dc.subject.keywordAuthor | Imidazol-5-ylpyrimidine | - |
dc.subject.keywordAuthor | MAPK14 | - |
dc.subject.keywordAuthor | Melanoma | - |
dc.subject.keywordAuthor | Molecular docking | - |
dc.subject.keywordAuthor | TNF-α | - |
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