{"title":"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。","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":"<p><strong>Aim: </strong>To develop potent B cell lymphoma 6 (BCL6) inhibitors, novel <i>N</i>-phenyl-4-pyrimidine-diamine analogs were designed and synthesized via structure-based and computer-aided drug design.</p><p><strong>Methods: </strong>Starting from the hit compound <b>ZB979</b>, we synthesized three series of pyrimidinediamine BCL6 inhibitors (<b>13a-13e, 14a-14c</b> and <b>15a-15g</b>) and evaluated their inhibitory activities on BCL6-SMRT interaction using homogeneous time-resolved fluorescence (HTRF) assays. The most promising candidate, compound <b>15d</b>, was further assessed for its anti-proliferative activity and modulation of BCL6 downstream target genes, suppression of germinal center (GC) formation.</p><p><strong>Results: </strong>Compound <b>15d</b> demonstrated significant BCL6-SMRT inhibition with favorable physicochemical properties (Calculated LogP (ClogP) and topological polar surface area (tPSA)).</p><p><strong>Conclusion: </strong>These findings highlight the potential of pyrimidinediamine-based scaffolds as novel BCL6 inhibitors, warranting further structural optimization to improve their efficacy.</p>","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":"{\"title\":\"Design and synthesis of novel <i>N</i>-phenyl-4-pyrimidine-diamine BCL6 inhibitors with <i>anti</i>-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\":\"<p><strong>Aim: </strong>To develop potent B cell lymphoma 6 (BCL6) inhibitors, novel <i>N</i>-phenyl-4-pyrimidine-diamine analogs were designed and synthesized via structure-based and computer-aided drug design.</p><p><strong>Methods: </strong>Starting from the hit compound <b>ZB979</b>, we synthesized three series of pyrimidinediamine BCL6 inhibitors (<b>13a-13e, 14a-14c</b> and <b>15a-15g</b>) and evaluated their inhibitory activities on BCL6-SMRT interaction using homogeneous time-resolved fluorescence (HTRF) assays. The most promising candidate, compound <b>15d</b>, was further assessed for its anti-proliferative activity and modulation of BCL6 downstream target genes, suppression of germinal center (GC) formation.</p><p><strong>Results: </strong>Compound <b>15d</b> demonstrated significant BCL6-SMRT inhibition with favorable physicochemical properties (Calculated LogP (ClogP) and topological polar surface area (tPSA)).</p><p><strong>Conclusion: </strong>These findings highlight the potential of pyrimidinediamine-based scaffolds as novel BCL6 inhibitors, warranting further structural optimization to improve their efficacy.</p>\",\"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}","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}
Design and synthesis of novel N-phenyl-4-pyrimidine-diamine BCL6 inhibitors with anti-tumor activities.
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.
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.
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