• 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

DPS-2：一种新型的双MEK/ERK和PI3K/AKT通路抑制剂，具有强大的体外和体内抗癌特性。

DPS-2: A Novel Dual MEK/ERK and PI3K/AKT Pathway Inhibitor with Powerful Ex Vivo and In Vivo Anticancer Properties.

作者信息

Goulielmaki Maria, Assimomytis Nikos, Rozanc Jan, Taki Eleni, Christodoulou Ioannis, Alexopoulos Leonidas G, Zoumpourlis Vassilis, Pintzas Alexandros, Papahatjis Demetris

机构信息

Institute of Biology Medicinal Chemistry and Biotechnology, National Hellenic Research Foundation, 116 36 Athens, Greece.

TEPA Lefkippos-Demokritos, Patriarchou Grigoriou & Neapoleos, 15343 Ag. Paraskevi, Attiki, Greece.

出版信息

Transl Oncol. 2019 Jul;12(7):932-950. doi: 10.1016/j.tranon.2019.04.005. Epub 2019 May 13.

DOI:10.1016/j.tranon.2019.04.005
PMID:31096110
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC6520640/
Abstract

Development of novel bioactive compounds against KRAS and/or BRAF mutant colorectal cancer (CRC) is currently an urgent need in oncology. In addition, single or multitarget kinase inhibitors against MEK/ERK and PI3K/AKT pathways are of potential therapeutic advantage. A new compound based on the benzothiophene nucleus was synthesized, based on previous important outcomes on other pharmaceutical preparations, to be tested as potential anticancer agent. Treatments by 2-5 μM DPS-2 of several CRC and melanoma cell lines bearing either BRAF or KRAS mutations have shown a remarkable effect on cell viability in 2D and 3D cultures. More detailed analysis has shown that DPS-2 can kill cancer cells by apoptosis, reducing at the same time their autophagy properties. After testing activities of several signaling pathways, the compound was found to have a dual inhibition of two major proliferative/survival pathways, MEK/ERK and PI3K/AKT, in both CRC and melanoma, thus providing a mechanistic evidence for its potent anticancer activity. Antitumor activity of DPS-2 was further validated in vivo, as DPS-2 treatment of mouse xenografts of Colo-205 colorectal cancer cells remarkably reduced their tumor formation properties. Our findings suggest that DPS-2 has significant anti-KRAS/ anti-BRAF mutant CRC activity in preclinical models, potentially providing a novel treatment strategy for these difficult-to-treat tumors, which needs to be further exploited.

摘要

开发针对KRAS和/或BRAF突变型结直肠癌（CRC）的新型生物活性化合物是肿瘤学领域当前的迫切需求。此外，针对MEK/ERK和PI3K/AKT通路的单靶点或多靶点激酶抑制剂具有潜在的治疗优势。基于之前在其他药物制剂上取得的重要成果，合成了一种基于苯并噻吩核的新化合物，以作为潜在的抗癌药物进行测试。用2 - 5 μM的DPS - 2处理几种携带BRAF或KRAS突变的CRC和黑色素瘤细胞系，已显示出在二维和三维培养中对细胞活力有显著影响。更详细的分析表明，DPS - 2可通过诱导凋亡杀死癌细胞，同时降低其自噬特性。在测试了几种信号通路的活性后，发现该化合物在CRC和黑色素瘤中对两条主要的增殖/存活通路MEK/ERK和PI3K/AKT具有双重抑制作用，从而为其强大的抗癌活性提供了机制证据。DPS - 2的抗肿瘤活性在体内进一步得到验证，因为用DPS - 2处理Colo - 205结直肠癌细胞的小鼠异种移植瘤显著降低了它们的肿瘤形成特性。我们的研究结果表明，DPS - 2在临床前模型中具有显著的抗KRAS/抗BRAF突变型CRC活性，可能为这些难以治疗的肿瘤提供一种新的治疗策略，这有待进一步探索。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2186/6520640/de227ea9e7b9/gr7.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2186/6520640/8423dbc154f8/gr1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2186/6520640/a32cea90b002/gr2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2186/6520640/e73600e3205e/gr3ab.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2186/6520640/4025d996d14d/gr4ad.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2186/6520640/dcc0c199af02/gr5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2186/6520640/024f8f85261b/gr6ab.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2186/6520640/de227ea9e7b9/gr7.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2186/6520640/8423dbc154f8/gr1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2186/6520640/a32cea90b002/gr2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2186/6520640/e73600e3205e/gr3ab.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2186/6520640/4025d996d14d/gr4ad.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2186/6520640/dcc0c199af02/gr5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2186/6520640/024f8f85261b/gr6ab.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2186/6520640/de227ea9e7b9/gr7.jpg

相似文献

1
DPS-2: A Novel Dual MEK/ERK and PI3K/AKT Pathway Inhibitor with Powerful Ex Vivo and In Vivo Anticancer Properties.DPS-2：一种新型的双MEK/ERK和PI3K/AKT通路抑制剂，具有强大的体外和体内抗癌特性。
Transl Oncol. 2019 Jul;12(7):932-950. doi: 10.1016/j.tranon.2019.04.005. Epub 2019 May 13.
2
Relationships among mutation status, expression of RAS pathway signaling molecules, and clinicopathological features and prognosis of patients with colorectal cancer.结直肠癌患者突变状态、RAS 通路信号分子表达与临床病理特征和预后的关系。
World J Gastroenterol. 2019 Feb 21;25(7):808-823. doi: 10.3748/wjg.v25.i7.808.
3
Pro-survival responses to the dual inhibition of anti-apoptotic Bcl-2 family proteins and mTOR-mediated signaling in hypoxic colorectal carcinoma cells.缺氧结直肠癌细胞中抗凋亡Bcl-2家族蛋白和mTOR介导的信号双重抑制的促生存反应
BMC Cancer. 2016 Jul 26;16:531. doi: 10.1186/s12885-016-2600-y.
4
Concomitant inhibition of receptor tyrosine kinases and downstream AKT synergistically inhibited growth of KRAS/BRAF mutant colorectal cancer cells.受体酪氨酸激酶和下游AKT的协同抑制可协同抑制KRAS/BRAF突变型结肠癌细胞的生长。
Oncotarget. 2017 Jan 17;8(3):5003-5015. doi: 10.18632/oncotarget.14009.
5
Primary cross-resistance to BRAFV600E-, MEK1/2- and PI3K/mTOR-specific inhibitors in BRAF-mutant melanoma cells counteracted by dual pathway blockade.BRAF 突变型黑色素瘤细胞对 BRAFV600E、MEK1/2 和 PI3K/mTOR 特异性抑制剂的原发性交叉耐药性可通过双重途径阻断来对抗。
Oncotarget. 2016 Jan 26;7(4):3947-65. doi: 10.18632/oncotarget.6600.
6
MEK plus PI3K/mTORC1/2 Therapeutic Efficacy Is Impacted by TP53 Mutation in Preclinical Models of Colorectal Cancer.在结直肠癌临床前模型中，MEK联合PI3K/mTORC1/2的治疗效果受TP53突变影响。
Clin Cancer Res. 2015 Dec 15;21(24):5499-5510. doi: 10.1158/1078-0432.CCR-14-3091. Epub 2015 Aug 13.
7
Antitumor activity of pimasertib, a selective MEK 1/2 inhibitor, in combination with PI3K/mTOR inhibitors or with multi-targeted kinase inhibitors in pimasertib-resistant human lung and colorectal cancer cells.帕米塞蒂布（一种选择性 MEK1/2 抑制剂）联合 PI3K/mTOR 抑制剂或多靶点激酶抑制剂在帕米塞蒂布耐药的人肺癌和结直肠癌细胞中的抗肿瘤活性。
Int J Cancer. 2013 Nov;133(9):2089-101. doi: 10.1002/ijc.28236. Epub 2013 May 29.
8
Delicaflavone induces ROS-mediated apoptosis and inhibits PI3K/AKT/mTOR and Ras/MEK/Erk signaling pathways in colorectal cancer cells.白皮杉醇诱导结直肠癌细胞中 ROS 介导的细胞凋亡，并抑制 PI3K/AKT/mTOR 和 Ras/MEK/Erk 信号通路。
Biochem Pharmacol. 2020 Jan;171:113680. doi: 10.1016/j.bcp.2019.113680. Epub 2019 Oct 25.
9
Dual Inhibition of MEK and PI3K Pathway in KRAS and BRAF Mutated Colorectal Cancers.KRAS和BRAF突变型结直肠癌中MEK和PI3K通路的双重抑制
Int J Mol Sci. 2015 Sep 23;16(9):22976-88. doi: 10.3390/ijms160922976.
10
Efficacy of the combination of MEK and CDK4/6 inhibitors in vitro and in vivo in KRAS mutant colorectal cancer models.MEK与CDK4/6抑制剂联合在KRAS突变型结直肠癌模型中的体内外疗效。
Oncotarget. 2016 Jun 28;7(26):39595-39608. doi: 10.18632/oncotarget.9153.

引用本文的文献

1
miR-29a-3p compositely regulates the COL6A6/PTEN-PI3K/Akt/CUX1 feedback loop to participate in the proliferation and invasion of pituitary adenomas.微小RNA-29a-3p通过复合调节COL6A6/PTEN-磷脂酰肌醇-3-激酶/蛋白激酶B/CUX1反馈环参与垂体腺瘤的增殖和侵袭。
J Mol Histol. 2025 May 27;56(3):172. doi: 10.1007/s10735-025-10436-0.
2
Navigating the ERK1/2 MAPK Cascade.ERK1/2 MAPK 级联途径的探索。
Biomolecules. 2023 Oct 20;13(10):1555. doi: 10.3390/biom13101555.
3
MEK inhibitors in cancer treatment: structural insights, regulation, recent advances and future perspectives.

本文引用的文献

1
Rational Approaches for Combination Therapy Strategies Targeting the MAP Kinase Pathway in Solid Tumors.针对实体瘤中 MAP 激酶通路的联合治疗策略的合理方法。
Mol Cancer Ther. 2018 Jan;17(1):3-16. doi: 10.1158/1535-7163.MCT-17-0349.
2
Dabrafenib plus trametinib in patients with previously untreated BRAF-mutant metastatic non-small-cell lung cancer: an open-label, phase 2 trial.达拉非尼联合曲美替尼治疗既往未经治疗的 BRAF 突变型转移性非小细胞肺癌的开放标签、2 期临床试验。
Lancet Oncol. 2017 Oct;18(10):1307-1316. doi: 10.1016/S1470-2045(17)30679-4. Epub 2017 Sep 11.
3
An overview of benzo[b]thiophene-based medicinal chemistry.
癌症治疗中的MEK抑制剂：结构见解、调控、最新进展及未来展望
RSC Med Chem. 2023 Aug 10;14(10):1837-1857. doi: 10.1039/d3md00145h. eCollection 2023 Oct 18.
4
Combining MEK and SRC inhibitors for treatment of colorectal cancer demonstrate increased efficacy in vitro but not in vivo.联合 MEK 和 SRC 抑制剂治疗结直肠癌在体外显示出更高的疗效，但在体内不行。
PLoS One. 2023 Mar 23;18(3):e0281063. doi: 10.1371/journal.pone.0281063. eCollection 2023.
5
Understanding autophagy role in cancer stem cell development.了解自噬在癌症干细胞发展中的作用。
Mol Biol Rep. 2022 Jul;49(7):6741-6751. doi: 10.1007/s11033-022-07299-z. Epub 2022 Mar 11.
6
Recent Developments in Targeting RAS Downstream Effectors for RAS-Driven Cancer Therapy.靶向 RAS 下游效应子治疗 RAS 驱动型癌症的最新进展。
Molecules. 2021 Dec 14;26(24):7561. doi: 10.3390/molecules26247561.
7
Biological Evaluation of Oil-in-Water Microemulsions as Carriers of Benzothiophene Analogues for Dermal Applications.水包油型微乳液作为苯并噻吩类似物皮肤应用载体的生物学评价
Biomimetics (Basel). 2021 Jan 27;6(1):10. doi: 10.3390/biomimetics6010010.
8
Blocking Y-Box Binding Protein-1 through Simultaneous Targeting of PI3K and MAPK in Triple Negative Breast Cancers.通过同时靶向PI3K和MAPK来阻断三阴性乳腺癌中的Y盒结合蛋白-1
Cancers (Basel). 2020 Sep 29;12(10):2795. doi: 10.3390/cancers12102795.
9
Tumor Suppressor Role of hsa-miR-193a-3p and -5p in Cutaneous Melanoma.hsa-miR-193a-3p 和 -5p 在皮肤黑色素瘤中的抑瘤作用。
Int J Mol Sci. 2020 Aug 27;21(17):6183. doi: 10.3390/ijms21176183.
10
COL6A6 interacted with P4HA3 to suppress the growth and metastasis of pituitary adenoma via blocking PI3K-Akt pathway.COL6A6与P4HA3相互作用，通过阻断PI3K-Akt信号通路来抑制垂体腺瘤的生长和转移。
Aging (Albany NY). 2019 Oct 17;11(20):8845-8859. doi: 10.18632/aging.102300.
苯并[b]噻吩类药物化学概述。
Eur J Med Chem. 2017 Sep 29;138:1002-1033. doi: 10.1016/j.ejmech.2017.07.038. Epub 2017 Jul 22.
4
Cobimetinib combined with vemurafenib in advanced BRAF(V600)-mutant melanoma (coBRIM): updated efficacy results from a randomised, double-blind, phase 3 trial.考比替尼联合维莫非尼治疗晚期 BRAF(V600)突变型黑色素瘤（coBRIM）：一项随机、双盲、III 期临床试验的更新疗效结果。
Lancet Oncol. 2016 Sep;17(9):1248-60. doi: 10.1016/S1470-2045(16)30122-X. Epub 2016 Jul 30.
5
Correlation between Gene Variants, Signaling Pathways, and Efficacy of Chemotherapy Drugs against Colon Cancers.基因变异、信号通路与化疗药物对结肠癌疗效之间的相关性
Cancer Inform. 2016 Jan 20;15:1-13. doi: 10.4137/CIN.S34506. eCollection 2016.
6
BRAF associated autophagy exploitation: BRAF and autophagy inhibitors synergise to efficiently overcome resistance of BRAF mutant colorectal cancer cells.BRAF相关的自噬利用：BRAF和自噬抑制剂协同作用，有效克服BRAF突变型结肠癌细胞的耐药性。
Oncotarget. 2016 Feb 23;7(8):9188-221. doi: 10.18632/oncotarget.6942.
7
Dual Inhibition of MEK and PI3K Pathway in KRAS and BRAF Mutated Colorectal Cancers.KRAS和BRAF突变型结直肠癌中MEK和PI3K通路的双重抑制
Int J Mol Sci. 2015 Sep 23;16(9):22976-88. doi: 10.3390/ijms160922976.
8
Combined BRAF and MEK Inhibition With Dabrafenib and Trametinib in BRAF V600-Mutant Colorectal Cancer.达拉非尼和曲美替尼联合抑制BRAF和MEK在BRAF V600突变型结直肠癌中的应用
J Clin Oncol. 2015 Dec 1;33(34):4023-31. doi: 10.1200/JCO.2015.63.2471. Epub 2015 Sep 21.
9
MEK inhibitors beyond monotherapy: current and future development.MEK抑制剂的联合治疗：现状与未来发展
Curr Opin Pharmacol. 2015 Aug;23:61-7. doi: 10.1016/j.coph.2015.05.012. Epub 2015 Jun 7.
10
Ramucirumab versus placebo in combination with second-line FOLFIRI in patients with metastatic colorectal carcinoma that progressed during or after first-line therapy with bevacizumab, oxaliplatin, and a fluoropyrimidine (RAISE): a randomised, double-blind, multicentre, phase 3 study.雷莫芦单抗联合 FOLFIRI 二线治疗用于贝伐珠单抗、奥沙利铂和氟嘧啶一线治疗后进展的转移性结直肠癌患者：一项随机、双盲、多中心、III 期研究（RAISE）。
Lancet Oncol. 2015 May;16(5):499-508. doi: 10.1016/S1470-2045(15)70127-0. Epub 2015 Apr 12.