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In silico identification of a novel Cdc2-like kinase 2 (CLK2) inhibitor in triple negative breast cancer.

التفاصيل البيبلوغرافية
العنوان: In silico identification of a novel Cdc2-like kinase 2 (CLK2) inhibitor in triple negative breast cancer.
المؤلفون: Huang CC; Ph.D. Program for Cancer Molecular Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University and Academia Sinica, Taipei, Taiwan.; Division of General Surgery, Department of Surgery, Taipei Medical University Hospital, Taipei, Taiwan.; Graduate Institute of Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan., Hsu CM; Graduate Institute of Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan., Chao MW; School of Medicine, College of Medicine, National Sun Yat-sen University, Kaohsiung, Taiwan.; Institute of Biopharmaceutical Sciences, College of Medicine, National Sun Yat-sen University, Kaohsiung, Taiwan.; The Doctoral Program of Clinical and Experimental Medicine, College of Medicine, National Sun Yat-sen University, Kaohsiung, Taiwan., Hsu KC; Ph.D. Program for Cancer Molecular Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University and Academia Sinica, Taipei, Taiwan.; Graduate Institute of Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan.; Ph.D. Program in Drug Discovery and Development Industry, College of Pharmacy, Taipei Medical University, Taipei, Taiwan.; TMU Research Center of Cancer Translational Medicine, Taipei Medical University, Taipei, Taiwan.; TMU Research Center of Drug Discovery, Taipei Medical University, Taipei, Taiwan., Lin TE; Ph.D. Program for Cancer Molecular Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University and Academia Sinica, Taipei, Taiwan.; Graduate Institute of Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan., Yen SC; Warshel Institute for Computational Biology, The Chinese University of Hong Kong (Shenzhen), Shenzhen, Guangdong, China., Tu HJ; Graduate Institute of Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan., Pan SL; Ph.D. Program for Cancer Molecular Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University and Academia Sinica, Taipei, Taiwan.; Graduate Institute of Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan.; Ph.D. Program in Drug Discovery and Development Industry, College of Pharmacy, Taipei Medical University, Taipei, Taiwan.; TMU Research Center of Cancer Translational Medicine, Taipei Medical University, Taipei, Taiwan.; TMU Research Center of Drug Discovery, Taipei Medical University, Taipei, Taiwan.
المصدر: Protein science : a publication of the Protein Society [Protein Sci] 2024 Jun; Vol. 33 (6), pp. e5004.
نوع المنشور: Journal Article; Research Support, Non-U.S. Gov't
اللغة: English
بيانات الدورية: Publisher: Cold Spring Harbor Laboratory Press Country of Publication: United States NLM ID: 9211750 Publication Model: Print Cited Medium: Internet ISSN: 1469-896X (Electronic) Linking ISSN: 09618368 NLM ISO Abbreviation: Protein Sci Subsets: MEDLINE
أسماء مطبوعة: Publication: 2001- : Woodbury, NY : Cold Spring Harbor Laboratory Press
Original Publication: New York, N.Y. : Cambridge University Press, c1992-
مواضيع طبية MeSH: Triple Negative Breast Neoplasms*/drug therapy , Triple Negative Breast Neoplasms*/metabolism , Protein Kinase Inhibitors*/pharmacology , Protein Kinase Inhibitors*/chemistry , Protein Serine-Threonine Kinases*/antagonists & inhibitors , Protein Serine-Threonine Kinases*/metabolism , Protein Serine-Threonine Kinases*/chemistry , Protein-Tyrosine Kinases*/antagonists & inhibitors , Protein-Tyrosine Kinases*/metabolism , Protein-Tyrosine Kinases*/chemistry , Protein-Tyrosine Kinases*/genetics, Humans ; Female ; Cell Line, Tumor ; Antineoplastic Agents/pharmacology ; Antineoplastic Agents/chemistry ; Apoptosis/drug effects ; Molecular Docking Simulation ; Cell Proliferation/drug effects
مستخلص: Dysregulation of RNA splicing processes is intricately linked to tumorigenesis in various cancers, especially breast cancer. Cdc2-like kinase 2 (CLK2), an oncogenic RNA-splicing kinase pivotal in breast cancer, plays a significant role, particularly in the context of triple-negative breast cancer (TNBC), a subtype marked by substantial medical challenges due to its low survival rates. In this study, we employed a structure-based virtual screening (SBVS) method to identify potential CLK2 inhibitors with novel chemical structures for treating TNBC. Compound 670551 emerged as a novel CLK2 inhibitor with a 50% inhibitory concentration (IC 50 ) value of 619.7 nM. Importantly, Compound 670551 exhibited high selectivity for CLK2 over other protein kinases. Functionally, this compound significantly reduced the survival and proliferation of TNBC cells. Results from a cell-based assay demonstrated that this inhibitor led to a decrease in RNA splicing proteins, such as SRSF4 and SRSF6, resulting in cell apoptosis. In summary, we identified a novel CLK2 inhibitor as a promising potential treatment for TNBC therapy.
(© 2024 The Authors. Protein Science published by Wiley Periodicals LLC on behalf of The Protein Society.)
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معلومات مُعتمدة: MOST 112-2320-B-038-052 Ministry of Science and Technology; AS-BRPT-112-11 Academia Sinica; TMU Research Center of Cancer Translational Medicine from the Higher Education Sprout Project by the Ministry of Education
فهرسة مساهمة: Keywords: CLK2; drug discovery; kinase inhibitor; structure‐based virtual screening; triple‐negative breast cancer
المشرفين على المادة: EC 2.7.1.- (Clk dual-specificity kinases)
0 (Protein Kinase Inhibitors)
EC 2.7.11.1 (Protein Serine-Threonine Kinases)
EC 2.7.10.1 (Protein-Tyrosine Kinases)
0 (Antineoplastic Agents)
تواريخ الأحداث: Date Created: 20240509 Date Completed: 20240509 Latest Revision: 20240626
رمز التحديث: 20240627
مُعرف محوري في PubMed: PMC11081522
DOI: 10.1002/pro.5004
PMID: 38723164
قاعدة البيانات: MEDLINE
الوصف
تدمد:1469-896X
DOI:10.1002/pro.5004