Design, in silico Evaluation, and Determination of Antitumor Activity of Potential Inhibitors Against Protein Kinases: Application to BCR-ABL Tyrosine Kinase

IF 2.3 4区生物学 Q3 BIOCHEMISTRY & MOLECULAR BIOLOGY Biochemistry (Moscow) Pub Date : 2024-07-04 DOI:10.1134/s0006297924060099

Elena V. Koroleva, Anastasiya L. Ermolinskaya, Zhanna V. Ignatovich, Yury V. Kornoushenko, Alesia V. Panibrat, Vladimir I. Potkin, Alexander M. Andrianov

{"title":"Design, in silico Evaluation, and Determination of Antitumor Activity of Potential Inhibitors Against Protein Kinases: Application to BCR-ABL Tyrosine Kinase","authors":"Elena V. Koroleva, Anastasiya L. Ermolinskaya, Zhanna V. Ignatovich, Yury V. Kornoushenko, Alesia V. Panibrat, Vladimir I. Potkin, Alexander M. Andrianov","doi":"10.1134/s0006297924060099","DOIUrl":null,"url":null,"abstract":"<h3 data-test=\"abstract-sub-heading\">Abstract</h3><p>Despite significant progress made over the past two decades in the treatment of chronic myeloid leukemia (CML), there is still an unmet need for effective and safe agents to treat patients with resistance and intolerance to the drugs used in clinic. In this work, we designed 2-arylaminopyrimidine amides of isoxazole-3-carboxylic acid, assessed <i>in silico</i> their inhibitory potential against Bcr-Abl tyrosine kinase, and determined their antitumor activity in K562 (CML), HL-60 (acute promyelocytic leukemia), and HeLa (cervical cancer) cells. Based on the analysis of computational and experimental data, three compounds with the antitumor activity against K562 and HL-60 cells were identified. The lead compound efficiently suppressed the growth of these cells, as evidenced by the low IC<sub>50</sub> values of 2.8 ± 0.8 μM (K562) and 3.5 ± 0.2 μM (HL-60). The obtained compounds represent promising basic structures for the design of novel, effective, and safe anticancer drugs able to inhibit the catalytic activity of Bcr-Abl kinase by blocking the ATP-binding site of the enzyme.</p>","PeriodicalId":483,"journal":{"name":"Biochemistry (Moscow)","volume":null,"pages":null},"PeriodicalIF":2.3000,"publicationDate":"2024-07-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Biochemistry (Moscow)","FirstCategoryId":"99","ListUrlMain":"https://doi.org/10.1134/s0006297924060099","RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q3","JCRName":"BIOCHEMISTRY & MOLECULAR BIOLOGY","Score":null,"Total":0}

引用次数: 0

Abstract

Despite significant progress made over the past two decades in the treatment of chronic myeloid leukemia (CML), there is still an unmet need for effective and safe agents to treat patients with resistance and intolerance to the drugs used in clinic. In this work, we designed 2-arylaminopyrimidine amides of isoxazole-3-carboxylic acid, assessed in silico their inhibitory potential against Bcr-Abl tyrosine kinase, and determined their antitumor activity in K562 (CML), HL-60 (acute promyelocytic leukemia), and HeLa (cervical cancer) cells. Based on the analysis of computational and experimental data, three compounds with the antitumor activity against K562 and HL-60 cells were identified. The lead compound efficiently suppressed the growth of these cells, as evidenced by the low IC₅₀ values of 2.8 ± 0.8 μM (K562) and 3.5 ± 0.2 μM (HL-60). The obtained compounds represent promising basic structures for the design of novel, effective, and safe anticancer drugs able to inhibit the catalytic activity of Bcr-Abl kinase by blocking the ATP-binding site of the enzyme.

Abstract Image

查看原文

微信好友朋友圈 QQ好友复制链接

本刊更多论文

蛋白激酶潜在抑制剂的设计、硅学评估和抗肿瘤活性的确定：对 BCR-ABL 酪氨酸激酶的应用

摘要尽管过去二十年来在治疗慢性粒细胞白血病（CML）方面取得了重大进展，但对有效和安全药物的需求仍未得到满足，以治疗对临床所用药物有耐药性和不耐受性的患者。在这项工作中，我们设计了异噁唑-3-羧酸的 2-芳基氨基嘧啶酰胺，对它们对 Bcr-Abl 酪氨酸激酶的抑制潜力进行了硅学评估，并测定了它们在 K562（CML）、HL-60（急性早幼粒细胞白血病）和 HeLa（宫颈癌）细胞中的抗肿瘤活性。根据计算和实验数据分析，确定了三种对 K562 和 HL-60 细胞具有抗肿瘤活性的化合物。先导化合物能有效抑制这些细胞的生长，其 IC50 值分别为 2.8 ± 0.8 μM （K562）和 3.5 ± 0.2 μM（HL-60）。这些化合物的基本结构很有希望设计出新型、有效、安全的抗癌药物，通过阻断酶的 ATP 结合位点来抑制 Bcr-Abl 激酶的催化活性。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

求助全文

约1分钟内获得全文去求助

来源期刊

Biochemistry (Moscow) 生物-生化与分子生物学

CiteScore

4.70

自引率

3.60%

发文量

139

审稿时长

2 months

期刊介绍： Biochemistry (Moscow) is the journal that includes research papers in all fields of biochemistry as well as biochemical aspects of molecular biology, bioorganic chemistry, microbiology, immunology, physiology, and biomedical sciences. Coverage also extends to new experimental methods in biochemistry, theoretical contributions of biochemical importance, reviews of contemporary biochemical topics, and mini-reviews (News in Biochemistry).