A novel amino-pyrimidine inhibitor suppresses tumor growth via microtubule destabilization and Bmi-1 down-regulation

IF 5.3 2区医学 Q1 PHARMACOLOGY & PHARMACY

Biochemical pharmacology Pub Date : 2025-01-27 DOI:10.1016/j.bcp.2025.116783

Lijie Gao , Jiawei Liu , Rui Zhang , Xi Chen , Mo Wang , Yujia Dong , Mykhaylo S. Frasinyuk , Wen Zhang , David Watt , Wenxiang Meng , Jun Xue , Chunming Liu , Yu Cheng , Xifu Liu

{"title":"A novel amino-pyrimidine inhibitor suppresses tumor growth via microtubule destabilization and Bmi-1 down-regulation","authors":"Lijie Gao , Jiawei Liu , Rui Zhang , Xi Chen , Mo Wang , Yujia Dong , Mykhaylo S. Frasinyuk , Wen Zhang , David Watt , Wenxiang Meng , Jun Xue , Chunming Liu , Yu Cheng , Xifu Liu","doi":"10.1016/j.bcp.2025.116783","DOIUrl":null,"url":null,"abstract":"<div><div>Colorectal cancer (CRC), one of the diseases posing a threat to global health, according to the latest data, is the third most common cancer globally and the second leading cause of cancer-related deaths. The development and refinement of novel structures of small molecular compounds play a crucial role in tumor treatment and overcoming drug resistance. In this study, our objective was to screen and characterize novel compounds for overcoming drug resistance <em>via</em> the B Lymphoma Mo-MLV insertion region 1 (Bmi-1) reporter screen assay. The stable cell line harboring the Bmi-1 reporter gene was utilized to screen 300 compounds, leading to the identification of an amino-pyrimidine compound, <strong>APD-94</strong>. <em>In vitro</em>, <strong>APD-94</strong> markedly inhibited cancer cell proliferation and decreased Bmi-1 expression at both the RNA and protein levels. <em>In vivo</em>, <strong>APD-94</strong> repressed the growth of HT29 cell xenografts in NOD/SCID mice without notable side effects. Flow cytometry results demonstrated that <strong>APD-94</strong> induced G2/M phase arrest and apoptosis in cells. <strong>APD-94</strong> was identified as a novel inhibitor of microtubule polymerization by directly targeting the tubulin. Furthermore, <strong>APD-94</strong> was more effective in overcoming the resistance to paclitaxel in paclitaxel-resistant A549/Tax cells. This bifunctional inhibitor is a promising candidate drug for CRC treatment.</div></div>","PeriodicalId":8806,"journal":{"name":"Biochemical pharmacology","volume":"233 ","pages":"Article 116783"},"PeriodicalIF":5.3000,"publicationDate":"2025-01-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Biochemical pharmacology","FirstCategoryId":"3","ListUrlMain":"https://www.sciencedirect.com/science/article/pii/S0006295225000450","RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"PHARMACOLOGY & PHARMACY","Score":null,"Total":0}

引用次数: 0

Abstract

Colorectal cancer (CRC), one of the diseases posing a threat to global health, according to the latest data, is the third most common cancer globally and the second leading cause of cancer-related deaths. The development and refinement of novel structures of small molecular compounds play a crucial role in tumor treatment and overcoming drug resistance. In this study, our objective was to screen and characterize novel compounds for overcoming drug resistance via the B Lymphoma Mo-MLV insertion region 1 (Bmi-1) reporter screen assay. The stable cell line harboring the Bmi-1 reporter gene was utilized to screen 300 compounds, leading to the identification of an amino-pyrimidine compound, APD-94. In vitro, APD-94 markedly inhibited cancer cell proliferation and decreased Bmi-1 expression at both the RNA and protein levels. In vivo, APD-94 repressed the growth of HT29 cell xenografts in NOD/SCID mice without notable side effects. Flow cytometry results demonstrated that APD-94 induced G2/M phase arrest and apoptosis in cells. APD-94 was identified as a novel inhibitor of microtubule polymerization by directly targeting the tubulin. Furthermore, APD-94 was more effective in overcoming the resistance to paclitaxel in paclitaxel-resistant A549/Tax cells. This bifunctional inhibitor is a promising candidate drug for CRC treatment.

Abstract Image

查看原文本刊更多论文

求助全文

约1分钟内获得全文求助全文

来源期刊

Biochemical pharmacology 医学-药学

CiteScore

10.30

自引率

1.70%

发文量

420

审稿时长

17 days

期刊介绍： Biochemical Pharmacology publishes original research findings, Commentaries and review articles related to the elucidation of cellular and tissue function(s) at the biochemical and molecular levels, the modification of cellular phenotype(s) by genetic, transcriptional/translational or drug/compound-induced modifications, as well as the pharmacodynamics and pharmacokinetics of xenobiotics and drugs, the latter including both small molecules and biologics. The journal''s target audience includes scientists engaged in the identification and study of the mechanisms of action of xenobiotics, biologics and drugs and in the drug discovery and development process. All areas of cellular biology and cellular, tissue/organ and whole animal pharmacology fall within the scope of the journal. Drug classes covered include anti-infectives, anti-inflammatory agents, chemotherapeutics, cardiovascular, endocrinological, immunological, metabolic, neurological and psychiatric drugs, as well as research on drug metabolism and kinetics. While medicinal chemistry is a topic of complimentary interest, manuscripts in this area must contain sufficient biological data to characterize pharmacologically the compounds reported. Submissions describing work focused predominately on chemical synthesis and molecular modeling will not be considered for review. While particular emphasis is placed on reporting the results of molecular and biochemical studies, research involving the use of tissue and animal models of human pathophysiology and toxicology is of interest to the extent that it helps define drug mechanisms of action, safety and efficacy.