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An innovative approach to development of new pyrazolylquinolin-2-one hybrids as dual EGFR and BRAF V600E inhibitors.

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Title: An innovative approach to development of new pyrazolylquinolin-2-one hybrids as dual EGFR and BRAF V600E inhibitors.
Authors: Hawwas MM; Department of Pharmaceutical Organic Chemistry, Faculty of Pharmacy, Al-Azhar University, Assiut, Egypt., Mancy AS; Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE, 68198, USA.; Department of Pharmaceutical Sciences, College of Pharmacy, University of Nebraska Medical Center, Omaha, Nebraska, USA., Ramadan M; Department of Pharmaceutical Organic Chemistry, Faculty of Pharmacy, Al-Azhar University, Assiut, Egypt. elbashamohammed@azhar.edu.eg., Ibrahim TS; Department of Pharmaceutical Chemistry, Faculty of Pharmacy, King Abdulaziz University, Jeddah, 21589, Saudi Arabia.; Department of Pharmaceutical Organic Chemistry, Faculty of Pharmacy, Zagazig University, Zagazig, 44519, Egypt., Bayoumi AH; Department of Pharmaceutical Organic Chemistry, Faculty of Pharmacy, Al-Azhar University, Cairo, Egypt., Alswah M; Department of Pharmaceutical Organic Chemistry, Faculty of Pharmacy, Al-Azhar University, Cairo, Egypt.
Source: Molecular diversity [Mol Divers] 2025 Dec; Vol. 29 (6), pp. 6379-6400. Date of Electronic Publication: 2025 Mar 08.
Publication Type: Journal Article
Language: English
Journal Info: Publisher: ESCOM Science Publishers Country of Publication: Netherlands NLM ID: 9516534 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1573-501X (Electronic) Linking ISSN: 13811991 NLM ISO Abbreviation: Mol Divers Subsets: MEDLINE
Imprint Name(s): Original Publication: Leiden, The Netherlands : ESCOM Science Publishers, c1995-
MeSH Terms: Proto-Oncogene Proteins B-raf*/antagonists & inhibitors , Proto-Oncogene Proteins B-raf*/genetics , Proto-Oncogene Proteins B-raf*/metabolism , ErbB Receptors*/antagonists & inhibitors , ErbB Receptors*/genetics , ErbB Receptors*/metabolism , Protein Kinase Inhibitors*/pharmacology , Protein Kinase Inhibitors*/chemistry , Protein Kinase Inhibitors*/chemical synthesis , Antineoplastic Agents*/pharmacology , Antineoplastic Agents*/chemistry , Antineoplastic Agents*/chemical synthesis , Quinolones*/chemistry , Quinolones*/pharmacology , Pyrazoles*/chemistry , Pyrazoles*/pharmacology, Humans ; Cell Line, Tumor ; Molecular Docking Simulation ; Cell Proliferation/drug effects ; Structure-Activity Relationship ; Apoptosis/drug effects ; Drug Screening Assays, Antitumor
Abstract: Competing Interests: Declarations. Conflict of interest: The authors declare no conflict of interest.
Novel quinoline-based derivatives 2a-e and 4a-j have been designed and synthesized as potential antiproliferative agents. The designed compounds were screened for their antiproliferative activity against sixty cell lines according to NCI protocol. The promising hybrids 4d-g are screened by MTT assays on three cancer cell lines: leukemia (MOLT-4), lung cancer (HOP-92), and breast cancer (T47D), with IC 50 values ranging from 4.982 ± 0.2 to 36.52 ± 1.46 µM compared to Staurosporine, with compound 4e being the most effective. Derivatives 4d-g were evaluated for their inhibitory activity on EGFR and BRAF V600E . Compound 4e exhibited the highest inhibitory activities, with IC 50 values of 0.055 ± 0.002 μM for EGFR and 0.068 ± 0.003 μM for BRAF V600E , compared to the reference drugs erlotinib (IC 50 0.06 ± 0.002 μM) and vemurafenib (IC 50 0.035 ± 0.001 μM), respectively. Cell cycle analysis of the HOP-92 manifested that pre-G1 apoptosis signaling took place after 4e treatment. Docking simulations were employed to analyze the modes and scores of compounds 4d-g with respect to EGFR and BRAF V600E . The results revealed that compound 4e exhibited strong affinity for both EGFR and BRAF V600E compared to the reference drugs with values of - 3.226 and - 3.474 kcal/mol, respectively.
(© 2025. The Author(s).)
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Contributed Indexing: Keywords: Antiproliferative; BRAFV600E; EGFR; Pyrazole; Quinoline
Substance Nomenclature: EC 2.7.11.1 (Proto-Oncogene Proteins B-raf)
EC 2.7.10.1 (ErbB Receptors)
0 (Protein Kinase Inhibitors)
0 (Antineoplastic Agents)
EC 2.7.10.1 (EGFR protein, human)
EC 2.7.11.1 (BRAF protein, human)
0 (Quinolones)
0 (Pyrazoles)
Entry Date(s): Date Created: 20250308 Date Completed: 20251121 Latest Revision: 20251124
Update Code: 20251124
PubMed Central ID: PMC12638379
DOI: 10.1007/s11030-025-11127-4
PMID: 40056327
Database: MEDLINE
Description
Abstract:Competing Interests: Declarations. Conflict of interest: The authors declare no conflict of interest.<br />Novel quinoline-based derivatives 2a-e and 4a-j have been designed and synthesized as potential antiproliferative agents. The designed compounds were screened for their antiproliferative activity against sixty cell lines according to NCI protocol. The promising hybrids 4d-g are screened by MTT assays on three cancer cell lines: leukemia (MOLT-4), lung cancer (HOP-92), and breast cancer (T47D), with IC <subscript>50</subscript> values ranging from 4.982 ± 0.2 to 36.52 ± 1.46 µM compared to Staurosporine, with compound 4e being the most effective. Derivatives 4d-g were evaluated for their inhibitory activity on EGFR and BRAF <sup>V600E</sup> . Compound 4e exhibited the highest inhibitory activities, with IC <subscript>50</subscript> values of 0.055 ± 0.002 μM for EGFR and 0.068 ± 0.003 μM for BRAF <sup>V600E</sup> , compared to the reference drugs erlotinib (IC <subscript>50</subscript> 0.06 ± 0.002 μM) and vemurafenib (IC <subscript>50</subscript> 0.035 ± 0.001 μM), respectively. Cell cycle analysis of the HOP-92 manifested that pre-G1 apoptosis signaling took place after 4e treatment. Docking simulations were employed to analyze the modes and scores of compounds 4d-g with respect to EGFR and BRAF <sup>V600E</sup> . The results revealed that compound 4e exhibited strong affinity for both EGFR and BRAF <sup>V600E</sup> compared to the reference drugs with values of - 3.226 and - 3.474 kcal/mol, respectively.<br /> (© 2025. The Author(s).)
ISSN:1573-501X
DOI:10.1007/s11030-025-11127-4