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Scaffold Repurposing of In-House Small Molecule Candidates Leads to Discovery of First-in-Class CDK-1/HER-2 Dual Inhibitors: In Vitro and In Silico Screening.

التفاصيل البيبلوغرافية
العنوان: Scaffold Repurposing of In-House Small Molecule Candidates Leads to Discovery of First-in-Class CDK-1/HER-2 Dual Inhibitors: In Vitro and In Silico Screening.
المؤلفون: Elkamhawy A; College of Pharmacy, Dongguk University-Seoul, Goyang 10326, Korea.; Department of Pharmaceutical Organic Chemistry, Faculty of Pharmacy, Mansoura University, Mansoura 35516, Egypt., Ammar UM; Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde, 161 Cathedral Street, Glasgow G4 0NR, UK., Paik S; Chemical Kinomics Research Center, Korea Institute of Science and Technology (KIST), Seoul 02792, Korea., Abdellattif MH; Department of Chemistry, College of Science, Taif University, P.O. Box 11099, Taif 21944, Saudi Arabia., Elsherbeny MH; Chemical Kinomics Research Center, Korea Institute of Science and Technology (KIST), Seoul 02792, Korea.; Division of Bio-Medical Science & Technology, KIST School, University of Science and Technology, Seoul 02792, Korea.; Pharmaceutical Chemistry Department, Faculty of Pharmacy, Ahram Canadian University, Giza 12566, Egypt., Lee K; College of Pharmacy, Dongguk University-Seoul, Goyang 10326, Korea., Roh EJ; Chemical Kinomics Research Center, Korea Institute of Science and Technology (KIST), Seoul 02792, Korea.; Division of Bio-Medical Science & Technology, KIST School, University of Science and Technology, Seoul 02792, Korea.
المصدر: Molecules (Basel, Switzerland) [Molecules] 2021 Sep 01; Vol. 26 (17). Date of Electronic Publication: 2021 Sep 01.
نوع المنشور: Journal Article
اللغة: English
بيانات الدورية: Publisher: MDPI Country of Publication: Switzerland NLM ID: 100964009 Publication Model: Electronic Cited Medium: Internet ISSN: 1420-3049 (Electronic) Linking ISSN: 14203049 NLM ISO Abbreviation: Molecules Subsets: MEDLINE
أسماء مطبوعة: Original Publication: Basel, Switzerland : MDPI, c1995-
مواضيع طبية MeSH: Drug Discovery*, Antineoplastic Agents/*pharmacology , Protein Kinase Inhibitors/*pharmacology , Small Molecule Libraries/*pharmacology, Antineoplastic Agents/chemical synthesis ; Antineoplastic Agents/chemistry ; CDC2 Protein Kinase ; Cell Line, Tumor ; Cell Proliferation/drug effects ; Cell Survival/drug effects ; Dose-Response Relationship, Drug ; Drug Evaluation, Preclinical ; Drug Screening Assays, Antitumor ; Humans ; Molecular Docking Simulation ; Molecular Structure ; Protein Kinase Inhibitors/chemical synthesis ; Protein Kinase Inhibitors/chemistry ; Receptor, ErbB-2 ; Small Molecule Libraries/chemical synthesis ; Small Molecule Libraries/chemistry ; Structure-Activity Relationship
مستخلص: Recently, multitargeted drugs are considered a potential approach in treating cancer. In this study, twelve in-house indole-based derivatives were preliminary evaluated for their inhibitory activities over VEGFR-2, CDK-1/cyclin B and HER-2. Compound 15l showed the most inhibitory activities among the tested derivatives over CDK-1/cyclin B and HER-2. Compound 15l was tested for its selectivity in a small kinase panel. It showed dual selectivity for CDK-1/cyclin B and HER-2. Moreover, in vitro cytotoxicity assay was assessed for the selected series against nine NCI cell lines. Compound 15l showed the most potent inhibitory activities among the tested compounds. A deep in silico molecular docking study was conducted for compound 15l to identify the possible binding modes into CDK-1/cyclin B and HER-2. The docking results revealed that compound 15l displayed interesting binding modes with the key amino acids in the binding sites of both kinases. In vitro and in silico studies demonstrate the indole-based derivative 15l as a selective dual CDK-1 and HER-2 inhibitor. This emphasizes a new challenge in drug development strategies and signals a significant milestone for further structural and molecular optimization of these indole-based derivatives in order to achieve a drug-like property.
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معلومات مُعتمدة: 2E31140 Korea Institute of Science and Technology; NRF-2018R1A5A2023127 National Research Foundation of Korea
فهرسة مساهمة: Keywords: CDK-1/cyclin B; HER-2; anti-cancer; anti-proliferative; drug repurposing; molecular docking
المشرفين على المادة: 0 (Antineoplastic Agents)
0 (Protein Kinase Inhibitors)
0 (Small Molecule Libraries)
EC 2.7.10.1 (ERBB2 protein, human)
EC 2.7.10.1 (Receptor, ErbB-2)
EC 2.7.11.22 (CDC2 Protein Kinase)
تواريخ الأحداث: Date Created: 20210910 Date Completed: 20211109 Latest Revision: 20211109
رمز التحديث: 20240829
مُعرف محوري في PubMed: PMC8433807
DOI: 10.3390/molecules26175324
PMID: 34500757
قاعدة البيانات: MEDLINE
الوصف
تدمد:1420-3049
DOI:10.3390/molecules26175324