Exploration of novel dihydroquinoxalinone derivatives as EGFR L858R/T790M tyrosine kinase inhibitors for the treatment of non-small-cell lung cancer

To overcome or delay the drug-resistance of first-generation epidermal growth factor receptor (EGFR) kinase inhibitors and non-selectivity toxicity mediated by second-generation inhibitors, splicing principle was employed to design and synthesize a series of Osimertinib derivatives containing dihydr...

Ausführliche Beschreibung

Gespeichert in:
Bibliographische Detailangaben
Veröffentlicht in:Bioorganic chemistry 2023-06, Vol.135, p.106494
Hauptverfasser: Cao, Yu, Lu, Xixuan, Fu, Liping, Shi, Tao, Zhang, Chong, Zeng, Linghui, Zhang, Jiankang, Shao, Jiaan, Xi, Jianjun, Pan, Zongfu, Liu, Shourong, Zhu, Huajian
Format: Artikel
Sprache:eng
Schlagworte:
Online-Zugang:Volltext
Tags: Tag hinzufügen
Keine Tags, Fügen Sie den ersten Tag hinzu!
container_end_page
container_issue
container_start_page 106494
container_title Bioorganic chemistry
container_volume 135
creator Cao, Yu
Lu, Xixuan
Fu, Liping
Shi, Tao
Zhang, Chong
Zeng, Linghui
Zhang, Jiankang
Shao, Jiaan
Xi, Jianjun
Pan, Zongfu
Liu, Shourong
Zhu, Huajian
description To overcome or delay the drug-resistance of first-generation epidermal growth factor receptor (EGFR) kinase inhibitors and non-selectivity toxicity mediated by second-generation inhibitors, splicing principle was employed to design and synthesize a series of Osimertinib derivatives containing dihydroquinoxalinone (8-30) as the novel third-generation inhibitors against double mutant L858R/T790M in EGFR. Among them, compound 29 showed excellent kinase inhibitory activity against EGFR with an IC value of 0.55 ± 0.02 nM and potent anti-proliferative activity against H1975 cells with an IC value of 5.88 ± 0.07 nM. Moreover, the strong down-regulation effect of EGFR-mediated signaling pathways and the promotion of apoptosis in H1975 cells confirmed its potent antitumor activities. Compound 29 was also demonstrated with good ADME profile in various in vitro assays. Further in vivo studies confirmed that compound 29 could suppress the growth of xenograft tumors. These results verified that compound 29 would be a promising lead compound for targeting drug-resistant EGFR mutations.
doi_str_mv 10.1016/j.bioorg.2023.106494
format Article
fullrecord <record><control><sourceid>pubmed</sourceid><recordid>TN_cdi_pubmed_primary_37011522</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><sourcerecordid>37011522</sourcerecordid><originalsourceid>FETCH-pubmed_primary_370115223</originalsourceid><addsrcrecordid>eNqFj01OwzAUhC0kRMvPDRB6F0hrO2nSrFEKC9hU3VdO8tK4OH7BdqLmHhyYSMCazcxo9EmjYexR8JXgIl2fV6UmcqeV5DKeqzTJkyu2FDznkRSSL9it92fOhUiy9IYt4myOGymX7Ku49IacCposUAOWRjRQ63aqHX0O2tJFmVktQo1OjzM4ogfloXjZ7eFtu9nu14cs5-8QJkdez-CHtsojaNvqUgdyHhpyEFqE4FCFDm34mbKR75QxUYXGgBnsCSplK3T37LpRxuPDr9-xp11xeH6N-qHssD72TnfKTce_G_G_wDeeNlwM</addsrcrecordid><sourcetype>Index Database</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype></control><display><type>article</type><title>Exploration of novel dihydroquinoxalinone derivatives as EGFR L858R/T790M tyrosine kinase inhibitors for the treatment of non-small-cell lung cancer</title><source>MEDLINE</source><source>Elsevier ScienceDirect Journals</source><creator>Cao, Yu ; Lu, Xixuan ; Fu, Liping ; Shi, Tao ; Zhang, Chong ; Zeng, Linghui ; Zhang, Jiankang ; Shao, Jiaan ; Xi, Jianjun ; Pan, Zongfu ; Liu, Shourong ; Zhu, Huajian</creator><creatorcontrib>Cao, Yu ; Lu, Xixuan ; Fu, Liping ; Shi, Tao ; Zhang, Chong ; Zeng, Linghui ; Zhang, Jiankang ; Shao, Jiaan ; Xi, Jianjun ; Pan, Zongfu ; Liu, Shourong ; Zhu, Huajian</creatorcontrib><description>To overcome or delay the drug-resistance of first-generation epidermal growth factor receptor (EGFR) kinase inhibitors and non-selectivity toxicity mediated by second-generation inhibitors, splicing principle was employed to design and synthesize a series of Osimertinib derivatives containing dihydroquinoxalinone (8-30) as the novel third-generation inhibitors against double mutant L858R/T790M in EGFR. Among them, compound 29 showed excellent kinase inhibitory activity against EGFR with an IC value of 0.55 ± 0.02 nM and potent anti-proliferative activity against H1975 cells with an IC value of 5.88 ± 0.07 nM. Moreover, the strong down-regulation effect of EGFR-mediated signaling pathways and the promotion of apoptosis in H1975 cells confirmed its potent antitumor activities. Compound 29 was also demonstrated with good ADME profile in various in vitro assays. Further in vivo studies confirmed that compound 29 could suppress the growth of xenograft tumors. These results verified that compound 29 would be a promising lead compound for targeting drug-resistant EGFR mutations.</description><identifier>EISSN: 1090-2120</identifier><identifier>DOI: 10.1016/j.bioorg.2023.106494</identifier><identifier>PMID: 37011522</identifier><language>eng</language><publisher>United States</publisher><subject>Antineoplastic Agents - pharmacology ; Antineoplastic Agents - therapeutic use ; Carcinoma, Non-Small-Cell Lung - pathology ; Cell Line, Tumor ; Cell Proliferation ; Drug Resistance, Neoplasm ; ErbB Receptors ; Humans ; Lung Neoplasms - pathology ; Mutation ; Protein Kinase Inhibitors - pharmacology ; Protein Kinase Inhibitors - therapeutic use ; Tyrosine Kinase Inhibitors</subject><ispartof>Bioorganic chemistry, 2023-06, Vol.135, p.106494</ispartof><rights>Copyright © 2023 Elsevier Inc. All rights reserved.</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,776,780,27903,27904</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/37011522$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Cao, Yu</creatorcontrib><creatorcontrib>Lu, Xixuan</creatorcontrib><creatorcontrib>Fu, Liping</creatorcontrib><creatorcontrib>Shi, Tao</creatorcontrib><creatorcontrib>Zhang, Chong</creatorcontrib><creatorcontrib>Zeng, Linghui</creatorcontrib><creatorcontrib>Zhang, Jiankang</creatorcontrib><creatorcontrib>Shao, Jiaan</creatorcontrib><creatorcontrib>Xi, Jianjun</creatorcontrib><creatorcontrib>Pan, Zongfu</creatorcontrib><creatorcontrib>Liu, Shourong</creatorcontrib><creatorcontrib>Zhu, Huajian</creatorcontrib><title>Exploration of novel dihydroquinoxalinone derivatives as EGFR L858R/T790M tyrosine kinase inhibitors for the treatment of non-small-cell lung cancer</title><title>Bioorganic chemistry</title><addtitle>Bioorg Chem</addtitle><description>To overcome or delay the drug-resistance of first-generation epidermal growth factor receptor (EGFR) kinase inhibitors and non-selectivity toxicity mediated by second-generation inhibitors, splicing principle was employed to design and synthesize a series of Osimertinib derivatives containing dihydroquinoxalinone (8-30) as the novel third-generation inhibitors against double mutant L858R/T790M in EGFR. Among them, compound 29 showed excellent kinase inhibitory activity against EGFR with an IC value of 0.55 ± 0.02 nM and potent anti-proliferative activity against H1975 cells with an IC value of 5.88 ± 0.07 nM. Moreover, the strong down-regulation effect of EGFR-mediated signaling pathways and the promotion of apoptosis in H1975 cells confirmed its potent antitumor activities. Compound 29 was also demonstrated with good ADME profile in various in vitro assays. Further in vivo studies confirmed that compound 29 could suppress the growth of xenograft tumors. These results verified that compound 29 would be a promising lead compound for targeting drug-resistant EGFR mutations.</description><subject>Antineoplastic Agents - pharmacology</subject><subject>Antineoplastic Agents - therapeutic use</subject><subject>Carcinoma, Non-Small-Cell Lung - pathology</subject><subject>Cell Line, Tumor</subject><subject>Cell Proliferation</subject><subject>Drug Resistance, Neoplasm</subject><subject>ErbB Receptors</subject><subject>Humans</subject><subject>Lung Neoplasms - pathology</subject><subject>Mutation</subject><subject>Protein Kinase Inhibitors - pharmacology</subject><subject>Protein Kinase Inhibitors - therapeutic use</subject><subject>Tyrosine Kinase Inhibitors</subject><issn>1090-2120</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2023</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqFj01OwzAUhC0kRMvPDRB6F0hrO2nSrFEKC9hU3VdO8tK4OH7BdqLmHhyYSMCazcxo9EmjYexR8JXgIl2fV6UmcqeV5DKeqzTJkyu2FDznkRSSL9it92fOhUiy9IYt4myOGymX7Ku49IacCposUAOWRjRQ63aqHX0O2tJFmVktQo1OjzM4ogfloXjZ7eFtu9nu14cs5-8QJkdez-CHtsojaNvqUgdyHhpyEFqE4FCFDm34mbKR75QxUYXGgBnsCSplK3T37LpRxuPDr9-xp11xeH6N-qHssD72TnfKTce_G_G_wDeeNlwM</recordid><startdate>202306</startdate><enddate>202306</enddate><creator>Cao, Yu</creator><creator>Lu, Xixuan</creator><creator>Fu, Liping</creator><creator>Shi, Tao</creator><creator>Zhang, Chong</creator><creator>Zeng, Linghui</creator><creator>Zhang, Jiankang</creator><creator>Shao, Jiaan</creator><creator>Xi, Jianjun</creator><creator>Pan, Zongfu</creator><creator>Liu, Shourong</creator><creator>Zhu, Huajian</creator><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope></search><sort><creationdate>202306</creationdate><title>Exploration of novel dihydroquinoxalinone derivatives as EGFR L858R/T790M tyrosine kinase inhibitors for the treatment of non-small-cell lung cancer</title><author>Cao, Yu ; Lu, Xixuan ; Fu, Liping ; Shi, Tao ; Zhang, Chong ; Zeng, Linghui ; Zhang, Jiankang ; Shao, Jiaan ; Xi, Jianjun ; Pan, Zongfu ; Liu, Shourong ; Zhu, Huajian</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-pubmed_primary_370115223</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2023</creationdate><topic>Antineoplastic Agents - pharmacology</topic><topic>Antineoplastic Agents - therapeutic use</topic><topic>Carcinoma, Non-Small-Cell Lung - pathology</topic><topic>Cell Line, Tumor</topic><topic>Cell Proliferation</topic><topic>Drug Resistance, Neoplasm</topic><topic>ErbB Receptors</topic><topic>Humans</topic><topic>Lung Neoplasms - pathology</topic><topic>Mutation</topic><topic>Protein Kinase Inhibitors - pharmacology</topic><topic>Protein Kinase Inhibitors - therapeutic use</topic><topic>Tyrosine Kinase Inhibitors</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Cao, Yu</creatorcontrib><creatorcontrib>Lu, Xixuan</creatorcontrib><creatorcontrib>Fu, Liping</creatorcontrib><creatorcontrib>Shi, Tao</creatorcontrib><creatorcontrib>Zhang, Chong</creatorcontrib><creatorcontrib>Zeng, Linghui</creatorcontrib><creatorcontrib>Zhang, Jiankang</creatorcontrib><creatorcontrib>Shao, Jiaan</creatorcontrib><creatorcontrib>Xi, Jianjun</creatorcontrib><creatorcontrib>Pan, Zongfu</creatorcontrib><creatorcontrib>Liu, Shourong</creatorcontrib><creatorcontrib>Zhu, Huajian</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><jtitle>Bioorganic chemistry</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Cao, Yu</au><au>Lu, Xixuan</au><au>Fu, Liping</au><au>Shi, Tao</au><au>Zhang, Chong</au><au>Zeng, Linghui</au><au>Zhang, Jiankang</au><au>Shao, Jiaan</au><au>Xi, Jianjun</au><au>Pan, Zongfu</au><au>Liu, Shourong</au><au>Zhu, Huajian</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Exploration of novel dihydroquinoxalinone derivatives as EGFR L858R/T790M tyrosine kinase inhibitors for the treatment of non-small-cell lung cancer</atitle><jtitle>Bioorganic chemistry</jtitle><addtitle>Bioorg Chem</addtitle><date>2023-06</date><risdate>2023</risdate><volume>135</volume><spage>106494</spage><pages>106494-</pages><eissn>1090-2120</eissn><abstract>To overcome or delay the drug-resistance of first-generation epidermal growth factor receptor (EGFR) kinase inhibitors and non-selectivity toxicity mediated by second-generation inhibitors, splicing principle was employed to design and synthesize a series of Osimertinib derivatives containing dihydroquinoxalinone (8-30) as the novel third-generation inhibitors against double mutant L858R/T790M in EGFR. Among them, compound 29 showed excellent kinase inhibitory activity against EGFR with an IC value of 0.55 ± 0.02 nM and potent anti-proliferative activity against H1975 cells with an IC value of 5.88 ± 0.07 nM. Moreover, the strong down-regulation effect of EGFR-mediated signaling pathways and the promotion of apoptosis in H1975 cells confirmed its potent antitumor activities. Compound 29 was also demonstrated with good ADME profile in various in vitro assays. Further in vivo studies confirmed that compound 29 could suppress the growth of xenograft tumors. These results verified that compound 29 would be a promising lead compound for targeting drug-resistant EGFR mutations.</abstract><cop>United States</cop><pmid>37011522</pmid><doi>10.1016/j.bioorg.2023.106494</doi></addata></record>
fulltext fulltext
identifier EISSN: 1090-2120
ispartof Bioorganic chemistry, 2023-06, Vol.135, p.106494
issn 1090-2120
language eng
recordid cdi_pubmed_primary_37011522
source MEDLINE; Elsevier ScienceDirect Journals
subjects Antineoplastic Agents - pharmacology
Antineoplastic Agents - therapeutic use
Carcinoma, Non-Small-Cell Lung - pathology
Cell Line, Tumor
Cell Proliferation
Drug Resistance, Neoplasm
ErbB Receptors
Humans
Lung Neoplasms - pathology
Mutation
Protein Kinase Inhibitors - pharmacology
Protein Kinase Inhibitors - therapeutic use
Tyrosine Kinase Inhibitors
title Exploration of novel dihydroquinoxalinone derivatives as EGFR L858R/T790M tyrosine kinase inhibitors for the treatment of non-small-cell lung cancer
url https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-01-28T01%3A05%3A39IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-pubmed&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Exploration%20of%20novel%20dihydroquinoxalinone%20derivatives%20as%20EGFR%20L858R/T790M%20tyrosine%20kinase%20inhibitors%20for%20the%20treatment%20of%20non-small-cell%20lung%20cancer&rft.jtitle=Bioorganic%20chemistry&rft.au=Cao,%20Yu&rft.date=2023-06&rft.volume=135&rft.spage=106494&rft.pages=106494-&rft.eissn=1090-2120&rft_id=info:doi/10.1016/j.bioorg.2023.106494&rft_dat=%3Cpubmed%3E37011522%3C/pubmed%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_id=info:pmid/37011522&rfr_iscdi=true