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

IF 4.5 3区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Protein Science Pub Date : 2024-06-01 DOI:10.1002/pro.5004
Cheng-Chiao Huang, Chia-Ming Hsu, Min-Wu Chao, Kai-Cheng Hsu, Tony Eight Lin, Shih-Chung Yen, Huang-Ju Tu, Shiow-Lin Pan
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Abstract

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 (IC50) 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.

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三阴性乳腺癌中新型 Cdc2 样激酶 2 (CLK2) 抑制剂的硅学鉴定。
RNA 剪接过程失调与各种癌症,尤其是乳腺癌的肿瘤发生密切相关。Cdc2样激酶2(CLK2)是一种致癌RNA剪接激酶,在乳腺癌中起着关键作用,尤其是在三阴性乳腺癌(TNBC)中。在这项研究中,我们采用了一种基于结构的虚拟筛选(SBVS)方法来鉴定具有新化学结构的潜在 CLK2 抑制剂,以治疗 TNBC。化合物 670551 是一种新型 CLK2 抑制剂,其 50% 抑制浓度 (IC50) 值为 619.7 nM。重要的是,与其他蛋白激酶相比,化合物 670551 对 CLK2 具有很高的选择性。在功能上,该化合物能显著降低 TNBC 细胞的存活率和增殖率。基于细胞的检测结果表明,这种抑制剂会导致 SRSF4 和 SRSF6 等 RNA 剪接蛋白的减少,从而导致细胞凋亡。总之,我们发现了一种新型 CLK2 抑制剂,它有望成为 TNBC 治疗的一种潜在疗法。
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来源期刊
Protein Science
Protein Science 生物-生化与分子生物学
CiteScore
12.40
自引率
1.20%
发文量
246
审稿时长
1 months
期刊介绍: Protein Science, the flagship journal of The Protein Society, is a publication that focuses on advancing fundamental knowledge in the field of protein molecules. The journal welcomes original reports and review articles that contribute to our understanding of protein function, structure, folding, design, and evolution. Additionally, Protein Science encourages papers that explore the applications of protein science in various areas such as therapeutics, protein-based biomaterials, bionanotechnology, synthetic biology, and bioelectronics. The journal accepts manuscript submissions in any suitable format for review, with the requirement of converting the manuscript to journal-style format only upon acceptance for publication. Protein Science is indexed and abstracted in numerous databases, including the Agricultural & Environmental Science Database (ProQuest), Biological Science Database (ProQuest), CAS: Chemical Abstracts Service (ACS), Embase (Elsevier), Health & Medical Collection (ProQuest), Health Research Premium Collection (ProQuest), Materials Science & Engineering Database (ProQuest), MEDLINE/PubMed (NLM), Natural Science Collection (ProQuest), and SciTech Premium Collection (ProQuest).
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