Development and biological evaluation of novel SOS1 inhibitors featuring 5,8-dihydropyrido[4,3-d]pyrimidin-7(6H)-one scaffold

IF 2.5 4区医学 Q3 CHEMISTRY, MEDICINAL

Bioorganic & Medicinal Chemistry Letters Pub Date : 2025-07-21 DOI:10.1016/j.bmcl.2025.130344

Xiaoyu Chen , Xuepei Ma , Zixuan Yang , Mei Mao , Wenjia Niu , Chengwei Zhang , Xiaolei Meng , Mengjun Ma , Zhuoyue Li , Xiao Wang , Shanshan Du , Shumin Ma , Siqi Zhang

{"title":"Development and biological evaluation of novel SOS1 inhibitors featuring 5,8-dihydropyrido[4,3-d]pyrimidin-7(6H)-one scaffold","authors":"Xiaoyu Chen , Xuepei Ma , Zixuan Yang , Mei Mao , Wenjia Niu , Chengwei Zhang , Xiaolei Meng , Mengjun Ma , Zhuoyue Li , Xiao Wang , Shanshan Du , Shumin Ma , Siqi Zhang","doi":"10.1016/j.bmcl.2025.130344","DOIUrl":null,"url":null,"abstract":"<div><div>SOS1 plays a pivotal role in RAS activation and has emerged as a promising therapeutic target for tumors driven by KRAS mutations. In this study, we designed and synthesized a novel series of SOS1 inhibitors based on the 5,8-dihydropyrido[4,3-<em>d</em>]pyrimidin-7(6<em>H</em>)-one scaffold. Biological evaluation revealed that most compounds displayed anti-proliferative activity against K562 leukemia cells. Among these, <strong>A15f</strong> and <strong>B5a</strong> emerged as the most potent compounds comparable to BI-3406. <strong>A15f</strong> and <strong>B5a</strong> exhibited inhibitory activity against KRAS-G12C/SOS1 complex formation, with IC₅₀ value of 40.28 and 11.11 nM respectively and led to a dose-dependent decrease in pERK levels. The combination therapy of KRAS G12C inhibitor and A15f shows enhanced <em>in vitro</em> efficacy. Molecular docking revealed that these two compounds shared a conserved binding mode with SOS1, similar to the reported inhibitors. These findings provide foundation for further development of SOS1-targeted anticancer therapeutics and offer valuable insights for structural optimization of this novel class of inhibitors.</div></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"128 ","pages":"Article 130344"},"PeriodicalIF":2.5000,"publicationDate":"2025-07-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Bioorganic & Medicinal Chemistry Letters","FirstCategoryId":"3","ListUrlMain":"https://www.sciencedirect.com/science/article/pii/S0960894X25002537","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

SOS1 plays a pivotal role in RAS activation and has emerged as a promising therapeutic target for tumors driven by KRAS mutations. In this study, we designed and synthesized a novel series of SOS1 inhibitors based on the 5,8-dihydropyrido[4,3-d]pyrimidin-7(6H)-one scaffold. Biological evaluation revealed that most compounds displayed anti-proliferative activity against K562 leukemia cells. Among these, A15f and B5a emerged as the most potent compounds comparable to BI-3406. A15f and B5a exhibited inhibitory activity against KRAS-G12C/SOS1 complex formation, with IC₅₀ value of 40.28 and 11.11 nM respectively and led to a dose-dependent decrease in pERK levels. The combination therapy of KRAS G12C inhibitor and A15f shows enhanced in vitro efficacy. Molecular docking revealed that these two compounds shared a conserved binding mode with SOS1, similar to the reported inhibitors. These findings provide foundation for further development of SOS1-targeted anticancer therapeutics and offer valuable insights for structural optimization of this novel class of inhibitors.

Abstract Image

查看原文本刊更多论文

以5,8-二氢吡啶[4,3-d]嘧啶-7(6H)- 1为支架的新型SOS1抑制剂的开发和生物学评价。

SOS1在RAS激活中起着关键作用，并已成为KRAS突变驱动的肿瘤的有希望的治疗靶点。在本研究中，我们设计并合成了一系列基于5,8-二氢吡啶[4,3-d]嘧啶-7(6H)- 1支架的新型SOS1抑制剂。生物学评价显示，大多数化合物对K562白血病细胞具有抗增殖活性。其中，A15f和B5a被认为是与BI-3406最有效的化合物。A15f和B5a对KRAS-G12C/SOS1复合物形成具有抑制活性，IC₅₀值分别为40.28和11.11 nM，并导致pERK水平呈剂量依赖性降低。KRAS G12C抑制剂与A15f联合治疗，体外疗效增强。分子对接发现，这两种化合物与SOS1具有保守的结合模式，与报道的抑制剂相似。这些发现为进一步开发sos1靶向抗癌药物提供了基础，并为这类新型抑制剂的结构优化提供了有价值的见解。

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

Bioorganic & Medicinal Chemistry Letters 医学-医药化学

CiteScore

5.70

自引率

3.70%

发文量

463

审稿时长

27 days

期刊介绍： Bioorganic & Medicinal Chemistry Letters presents preliminary experimental or theoretical research results of outstanding significance and timeliness on all aspects of science at the interface of chemistry and biology and on major advances in drug design and development. The journal publishes articles in the form of communications reporting experimental or theoretical results of special interest, and strives to provide maximum dissemination to a large, international audience.