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...
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Veröffentlicht in: | Bioorganic chemistry 2023-06, Vol.135, p.106494 |
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container_title | Bioorganic chemistry |
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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 |
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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> |
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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 |
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