Design and synthesis of novel N-phenyl-4-pyrimidine-diamine BCL6 inhibitors with anti-tumor activities.

IF 3.4 4区医学 Q3 CHEMISTRY, MEDICINAL

Future medicinal chemistry Pub Date : 2025-09-21 DOI:10.1080/17568919.2025.2561541

Yan Li, Yajing Xing, Dongxia Huang, Jiuqing Xie, Yangrui Peng, Zhengfang Yi, Yihua Chen

{"title":"Design and synthesis of novel N-phenyl-4-pyrimidine-diamine BCL6 inhibitors with anti-tumor activities.","authors":"Yan Li, Yajing Xing, Dongxia Huang, Jiuqing Xie, Yangrui Peng, Zhengfang Yi, Yihua Chen","doi":"10.1080/17568919.2025.2561541","DOIUrl":null,"url":null,"abstract":"Aim: To develop potent B cell lymphoma 6 (BCL6) inhibitors, novel N-phenyl-4-pyrimidine-diamine analogs were designed and synthesized via structure-based and computer-aided drug design.Methods: Starting from the hit compound ZB979, we synthesized three series of pyrimidinediamine BCL6 inhibitors (13a-13e, 14a-14c and 15a-15g) and evaluated their inhibitory activities on BCL6-SMRT interaction using homogeneous time-resolved fluorescence (HTRF) assays. The most promising candidate, compound 15d, was further assessed for its anti-proliferative activity and modulation of BCL6 downstream target genes, suppression of germinal center (GC) formation.Results: Compound 15d demonstrated significant BCL6-SMRT inhibition with favorable physicochemical properties (Calculated LogP (ClogP) and topological polar surface area (tPSA)).Conclusion: These findings highlight the potential of pyrimidinediamine-based scaffolds as novel BCL6 inhibitors, warranting further structural optimization to improve their efficacy.","PeriodicalId":12475,"journal":{"name":"Future medicinal chemistry","volume":" ","pages":"1-12"},"PeriodicalIF":3.4000,"publicationDate":"2025-09-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Future medicinal chemistry","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1080/17568919.2025.2561541","RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q3","JCRName":"CHEMISTRY, MEDICINAL","Score":null,"Total":0}

引用次数: 0

Abstract

Aim: To develop potent B cell lymphoma 6 (BCL6) inhibitors, novel N-phenyl-4-pyrimidine-diamine analogs were designed and synthesized via structure-based and computer-aided drug design.

Methods: Starting from the hit compound ZB979, we synthesized three series of pyrimidinediamine BCL6 inhibitors (13a-13e, 14a-14c and 15a-15g) and evaluated their inhibitory activities on BCL6-SMRT interaction using homogeneous time-resolved fluorescence (HTRF) assays. The most promising candidate, compound 15d, was further assessed for its anti-proliferative activity and modulation of BCL6 downstream target genes, suppression of germinal center (GC) formation.

Results: Compound 15d demonstrated significant BCL6-SMRT inhibition with favorable physicochemical properties (Calculated LogP (ClogP) and topological polar surface area (tPSA)).

Conclusion: These findings highlight the potential of pyrimidinediamine-based scaffolds as novel BCL6 inhibitors, warranting further structural optimization to improve their efficacy.

查看原文本刊更多论文

具有抗肿瘤活性的新型n -苯基-4-嘧啶-二胺BCL6抑制剂的设计与合成。

目的：采用基于结构和计算机辅助药物设计的方法，设计合成了新型n -苯基-4-嘧啶-二胺类似物，以开发有效的B细胞淋巴瘤6 （BCL6）抑制剂。方法：从命中的化合物ZB979开始，合成了3个系列的嘧啶二胺类BCL6抑制剂（13a-13e、14a-14c和15a-15g），并采用均匀时间分辨荧光法（htf）评价了它们对BCL6- smrt相互作用的抑制活性。最有希望的候选化合物15d被进一步评估其抗增殖活性和BCL6下游靶基因的调节，抑制生发中心（GC）的形成。结果：化合物15d表现出明显的BCL6-SMRT抑制作用，具有良好的理化性质（计算LogP （ClogP）和拓扑极性表面积（tPSA））。结论：这些发现突出了嘧啶二胺基支架作为新型BCL6抑制剂的潜力，需要进一步优化结构以提高其疗效。

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分钟内获得全文求助全文

来源期刊

Future medicinal chemistry CHEMISTRY, MEDICINAL-

CiteScore

5.80

自引率

2.40%

发文量

118

审稿时长

4-8 weeks

期刊介绍： Future Medicinal Chemistry offers a forum for the rapid publication of original research and critical reviews of the latest milestones in the field. Strong emphasis is placed on ensuring that the journal stimulates awareness of issues that are anticipated to play an increasingly central role in influencing the future direction of pharmaceutical chemistry. Where relevant, contributions are also actively encouraged on areas as diverse as biotechnology, enzymology, green chemistry, genomics, immunology, materials science, neglected diseases and orphan drugs, pharmacogenomics, proteomics and toxicology.