• 文献检索
  • 文档翻译
  • 深度研究
  • 学术资讯
  • Suppr Zotero 插件Zotero 插件
  • 邀请有礼
  • 套餐&价格
  • 历史记录
应用&插件
Suppr Zotero 插件Zotero 插件浏览器插件Mac 客户端Windows 客户端微信小程序
定价
高级版会员购买积分包购买API积分包
服务
文献检索文档翻译深度研究API 文档MCP 服务
关于我们
关于 Suppr公司介绍联系我们用户协议隐私条款
关注我们

Suppr 超能文献

核心技术专利：CN118964589B侵权必究
粤ICP备2023148730 号-1Suppr @ 2026

文献检索

告别复杂PubMed语法，用中文像聊天一样搜索，搜遍4000万医学文献。AI智能推荐，让科研检索更轻松。

立即免费搜索

文件翻译

保留排版，准确专业，支持PDF/Word/PPT等文件格式，支持 12+语言互译。

免费翻译文档

深度研究

AI帮你快速写综述，25分钟生成高质量综述，智能提取关键信息，辅助科研写作。

立即免费体验

发现具有良好药代动力学特征和体内抗癌疗效的 CDC42 抑制剂。

Discovery of CDC42 Inhibitors with a Favorable Pharmacokinetic Profile and Anticancer In Vivo Efficacy.

机构信息

Molecular Modeling and Drug Discovery Lab, Istituto Italiano di Tecnologia, via Morego 30, 16163 Genova, Italy.

Department of Dermatology, University of California, Irvine, California 92697, United States.

出版信息

J Med Chem. 2024 Jun 27;67(12):10401-10424. doi: 10.1021/acs.jmedchem.4c00855. Epub 2024 Jun 12.

DOI:10.1021/acs.jmedchem.4c00855
PMID:38866385
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11215724/
Abstract

We previously reported trisubstituted pyrimidine lead compounds, namely, ARN22089 and ARN25062, which block the interaction between CDC42 with its specific downstream effector, a PAK protein. This interaction is crucial for the progression of multiple tumor types. Such inhibitors showed anticancer efficacy in vivo. Here, we describe a second class of CDC42 inhibitors with favorable drug-like properties. Out of the 25 compounds here reported, compound (ARN25499) stands out as the best lead compound with an improved pharmacokinetic profile, increased bioavailability, and efficacy in an in vivo PDX tumor mouse model. Our results indicate that these CDC42 inhibitors represent a promising chemical class toward the discovery of anticancer drugs, with ARN25499 as an additional lead candidate for preclinical development.

摘要

我们之前报道了三取代嘧啶先导化合物，即 ARN22089 和 ARN25062，它们可阻断 CDC42 与其特定下游效应物 PAK 蛋白之间的相互作用。这种相互作用对于多种肿瘤类型的进展至关重要。这些抑制剂在体内显示出抗癌功效。在这里，我们描述了第二类具有良好药物特性的 CDC42 抑制剂。在所报道的 25 种化合物中，化合物 (ARN25499) 脱颖而出，成为最佳先导化合物，具有改善的药代动力学特性、更高的生物利用度和在体内 PDX 肿瘤小鼠模型中的疗效。我们的结果表明，这些 CDC42 抑制剂代表了一类有前途的抗癌药物化学物质，ARN25499 是临床前开发的另一个候选先导药物。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6779/11215724/f9dff557de57/jm4c00855_0010.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6779/11215724/b07097688a65/jm4c00855_0001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6779/11215724/342ed360b811/jm4c00855_0002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6779/11215724/848aaf3dca85/jm4c00855_0003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6779/11215724/656b7ae25b6b/jm4c00855_0004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6779/11215724/03eb80b5c564/jm4c00855_0005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6779/11215724/2419c7dacfd9/jm4c00855_0006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6779/11215724/d953f18572c8/jm4c00855_0007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6779/11215724/495f69618951/jm4c00855_0008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6779/11215724/f56ec72d8a50/jm4c00855_0009.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6779/11215724/f9dff557de57/jm4c00855_0010.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6779/11215724/b07097688a65/jm4c00855_0001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6779/11215724/342ed360b811/jm4c00855_0002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6779/11215724/848aaf3dca85/jm4c00855_0003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6779/11215724/656b7ae25b6b/jm4c00855_0004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6779/11215724/03eb80b5c564/jm4c00855_0005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6779/11215724/2419c7dacfd9/jm4c00855_0006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6779/11215724/d953f18572c8/jm4c00855_0007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6779/11215724/495f69618951/jm4c00855_0008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6779/11215724/f56ec72d8a50/jm4c00855_0009.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6779/11215724/f9dff557de57/jm4c00855_0010.jpg

相似文献

1
Discovery of CDC42 Inhibitors with a Favorable Pharmacokinetic Profile and Anticancer In Vivo Efficacy.发现具有良好药代动力学特征和体内抗癌疗效的 CDC42 抑制剂。
J Med Chem. 2024 Jun 27;67(12):10401-10424. doi: 10.1021/acs.jmedchem.4c00855. Epub 2024 Jun 12.
2
Discovery and synthesis of azepinoindoles as novel hCYP1B1 inhibitors with AhR-independent anticancer activity.氮杂环庚三烯并吲哚类化合物作为具有不依赖芳烃受体的抗癌活性的新型人细胞色素P450 1B1抑制剂的发现与合成。
Bioorg Chem. 2025 Aug;163:108786. doi: 10.1016/j.bioorg.2025.108786. Epub 2025 Jul 21.
3
Factors Influencing the Central Nervous System (CNS) Distribution of the Ataxia Telangiectasia Mutated and Rad3-Related Inhibitor Elimusertib (BAY1895344): Implications for the Treatment of CNS Tumors.影响共济失调毛细血管扩张突变和 Rad3 相关抑制剂依鲁替尼（BAY1895344）在中枢神经系统（CNS）分布的因素：对中枢神经系统肿瘤治疗的影响。
J Pharmacol Exp Ther. 2024 Oct 18;391(2):346-360. doi: 10.1124/jpet.123.002002.
4
Anticancer and Antibacterial Activeness of Fused Pyrimidines: Newfangled Updates.稠合嘧啶的抗癌和抗菌活性：最新进展
Bioorg Chem. 2024 Dec;153:107780. doi: 10.1016/j.bioorg.2024.107780. Epub 2024 Sep 3.
5
Development of 9-cinnamyl-9H-purine derivatives as potent anticancer agents through inactivation of NF-κb/p65 and p-STAT1 signaling pathways: Discovery of a new template for adenosine receptor.通过使NF-κb/p65和p-STAT1信号通路失活开发9-肉桂基-9H-嘌呤衍生物作为强效抗癌剂：发现腺苷受体的新模板
Bioorg Chem. 2025 Aug;163:108647. doi: 10.1016/j.bioorg.2025.108647. Epub 2025 May 31.
6
Systemic treatments for metastatic cutaneous melanoma.转移性皮肤黑色素瘤的全身治疗
Cochrane Database Syst Rev. 2018 Feb 6;2(2):CD011123. doi: 10.1002/14651858.CD011123.pub2.
7
Design, synthesis and biological evaluation of (E)-4-(2-((1H-indol-5-yl) methylene) hydrazineyl)-5,6,7,8-tetrahydropyrido [4',3':4,5] thieno[2,3-d] pyrimidine derivatives as Arf1-GEFs inhibitors for the treatment of colon cancer.作为用于治疗结肠癌的Arf1-GEFs抑制剂的(E)-4-(2-((1H-吲哚-5-基)亚甲基)肼基)-5,6,7,8-四氢吡啶并[4',3':4,5]噻吩并[2,3-d]嘧啶衍生物的设计、合成及生物学评价
Eur J Med Chem. 2025 Nov 5;297:117962. doi: 10.1016/j.ejmech.2025.117962. Epub 2025 Jul 11.
8
Synthesis of Novel Derivatives of 4,6-Diarylpyrimidines and Dihydro-Pyrimidin-4-one and Screening of Their Anticancer Activity.4,6-二芳基嘧啶和二氢嘧啶-4-酮的新型衍生物的合成及其抗癌活性筛选
Curr Org Synth. 2025;22(4):556-567. doi: 10.2174/0115701794356958241024082646.
9
The Black Book of Psychotropic Dosing and Monitoring.《精神药物剂量与监测黑皮书》
Psychopharmacol Bull. 2024 Jul 8;54(3):8-59.
10
Discovery and Optimization of Potent PROTAC Degraders of Phosphoinositide 3-Kinase with Significant Anticancer Efficacy.具有显著抗癌功效的磷酸肌醇3-激酶强效PROTAC降解剂的发现与优化
J Med Chem. 2025 Jun 26;68(12):12800-12818. doi: 10.1021/acs.jmedchem.5c00679. Epub 2025 Jun 15.

本文引用的文献

1
Design, Synthesis, and Characterization of CDC42 GTPase Interaction Inhibitors for the Treatment of Cancer.设计、合成和鉴定 CDC42 GTPase 相互作用抑制剂用于癌症治疗。
J Med Chem. 2023 Apr 27;66(8):5981-6001. doi: 10.1021/acs.jmedchem.3c00276. Epub 2023 Apr 7.
2
Structure-Activity Relationships of Pyrimidine Derivatives and their Biological Activity - A Review.嘧啶衍生物的构效关系及其生物活性——综述
Med Chem. 2022;19(1):10-30. doi: 10.2174/1573406418666220509100356.
3
Structure-based design of CDC42 effector interaction inhibitors for the treatment of cancer.
基于结构设计CDC42效应器相互作用抑制剂用于癌症治疗
Cell Rep. 2022 Apr 26;39(4):110760. doi: 10.1016/j.celrep.2022.110760.
4
Fragment-Based Drug Discovery by NMR. Where Are the Successes and Where can It Be Improved?基于核磁共振的片段药物发现。成功之处何在，又该如何改进？
Front Mol Biosci. 2022 Feb 18;9:834453. doi: 10.3389/fmolb.2022.834453. eCollection 2022.
5
Could cell division cycle protein 42 be a target for lung cancer treatment?细胞分裂周期蛋白42能否成为肺癌治疗的靶点？
Transl Cancer Res. 2019 Feb;8(1):312-318. doi: 10.21037/tcr.2019.01.13.
6
Molecular subversion of Cdc42 signalling in cancer.癌组织中 Cdc42 信号的分子颠覆。
Biochem Soc Trans. 2021 Jun 30;49(3):1425-1442. doi: 10.1042/BST20200557.
7
Progress in the therapeutic inhibition of Cdc42 signalling.Cdc42 信号转导治疗抑制的研究进展。
Biochem Soc Trans. 2021 Jun 30;49(3):1443-1456. doi: 10.1042/BST20210112.
8
Targeting Rac and Cdc42 GEFs in Metastatic Cancer.靶向转移性癌症中的Rac和Cdc42鸟嘌呤核苷酸交换因子
Front Cell Dev Biol. 2020 Apr 8;8:201. doi: 10.3389/fcell.2020.00201. eCollection 2020.
9
Systems analysis of RhoGEF and RhoGAP regulatory proteins reveals spatially organized RAC1 signalling from integrin adhesions.系统分析 RhoGEF 和 RhoGAP 调节蛋白揭示了整合素黏附中空间组织的 Rac1 信号。
Nat Cell Biol. 2020 Apr;22(4):498-511. doi: 10.1038/s41556-020-0488-x. Epub 2020 Mar 23.
10
A novel interplay between GEFs orchestrates Cdc42 activity during cell polarity and cytokinesis in fission yeast.一种新型的 GEFs 相互作用在有丝分裂酵母的细胞极性和胞质分裂过程中调节 Cdc42 的活性。
J Cell Sci. 2019 Dec 3;132(23):jcs236018. doi: 10.1242/jcs.236018.