Design, synthesis and evaluation of new pyrimidine derivatives as EGFR C797S tyrosine kinase inhibitors
The clinical use of epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) in the treatment of non-small cell lung cancer was limited by the drug resistance caused by EGFR mutation. Therefore, in order to overcome the drug resistance, we designed and synthesized a series of 2-aminop...
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| Veröffentlicht in: | Bioorganic & medicinal chemistry letters 2023-07, Vol.91, p.129381 |
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| creator | Mao, Yu-Ze Xi, Xiao-Xiao Zhao, Hong-Yi Zhang, Yin-Liang Zhang, San-Qi |
| description | The clinical use of epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) in the treatment of non-small cell lung cancer was limited by the drug resistance caused by EGFR
mutation. Therefore, in order to overcome the drug resistance, we designed and synthesized a series of 2-aminopyrimidine derivatives as EGFR
-TKIs. Among these compounds, compounds A5 and A13 showed significant anti-proliferative activity against the KC-0116 (EGFR
) cell line with high selectivity. A5 inhibited EGFR phosphorylation and induced apoptosis of KC-0116 cell, arrested KC-0116 cell at G2/M phase. Molecular docking results showed that A5 and brigatinib bind to EGFR in a similar pattern. In addition to forming two important hydrogen bonds with Met793 residue, A5 also formed a hydrogen bond with Lys745 residues, which may play an important role for the potent inhibitory activity against EGFR
. Based on these results, A5 turned out to be effective reversible EGFR
-TKIs which can be further developed. |
| doi_str_mv | 10.1016/j.bmcl.2023.129381 |
| format | Article |
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mutation. Therefore, in order to overcome the drug resistance, we designed and synthesized a series of 2-aminopyrimidine derivatives as EGFR
-TKIs. Among these compounds, compounds A5 and A13 showed significant anti-proliferative activity against the KC-0116 (EGFR
) cell line with high selectivity. A5 inhibited EGFR phosphorylation and induced apoptosis of KC-0116 cell, arrested KC-0116 cell at G2/M phase. Molecular docking results showed that A5 and brigatinib bind to EGFR in a similar pattern. In addition to forming two important hydrogen bonds with Met793 residue, A5 also formed a hydrogen bond with Lys745 residues, which may play an important role for the potent inhibitory activity against EGFR
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mutation. Therefore, in order to overcome the drug resistance, we designed and synthesized a series of 2-aminopyrimidine derivatives as EGFR
-TKIs. Among these compounds, compounds A5 and A13 showed significant anti-proliferative activity against the KC-0116 (EGFR
) cell line with high selectivity. A5 inhibited EGFR phosphorylation and induced apoptosis of KC-0116 cell, arrested KC-0116 cell at G2/M phase. Molecular docking results showed that A5 and brigatinib bind to EGFR in a similar pattern. In addition to forming two important hydrogen bonds with Met793 residue, A5 also formed a hydrogen bond with Lys745 residues, which may play an important role for the potent inhibitory activity against EGFR
. Based on these results, A5 turned out to be effective reversible EGFR
-TKIs which can be further developed.</description><subject>Antineoplastic Agents - chemistry</subject><subject>Carcinoma, Non-Small-Cell Lung - drug therapy</subject><subject>Drug Resistance, Neoplasm</subject><subject>ErbB Receptors</subject><subject>Humans</subject><subject>Lung Neoplasms - drug therapy</subject><subject>Molecular Docking Simulation</subject><subject>Mutation</subject><subject>Protein Kinase Inhibitors - chemistry</subject><subject>Pyrimidines - chemistry</subject><subject>Tyrosine Kinase Inhibitors</subject><issn>1464-3405</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2023</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqFjs1ugzAQhK1KVZI2fYEeqn2AhNrYhXDOX89t7siEhWwKBnkJEW9fIjXnnuaT5tNohHhVMlBSRe_nIKuPVRDKUAcqTPRKPYiZMpFZaiM_puKJ-SylMtKYiZjqWOvIqGQmyg0ylW4BPLjuNDKDdTlgb6uL7ahx0BTg8Art4KmmnBxCjp76sexxlBm2-90XrOMk_oZu8A3flB9ylhHInSijrvE8F4-FrRhf_vJZvO22h_Xnsr1kNeZpO65bP6T3Z_pf4Re4tEqu</recordid><startdate>20230715</startdate><enddate>20230715</enddate><creator>Mao, Yu-Ze</creator><creator>Xi, Xiao-Xiao</creator><creator>Zhao, Hong-Yi</creator><creator>Zhang, Yin-Liang</creator><creator>Zhang, San-Qi</creator><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope></search><sort><creationdate>20230715</creationdate><title>Design, synthesis and evaluation of new pyrimidine derivatives as EGFR C797S tyrosine kinase inhibitors</title><author>Mao, Yu-Ze ; Xi, Xiao-Xiao ; Zhao, Hong-Yi ; Zhang, Yin-Liang ; Zhang, San-Qi</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-pubmed_primary_373364193</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2023</creationdate><topic>Antineoplastic Agents - chemistry</topic><topic>Carcinoma, Non-Small-Cell Lung - drug therapy</topic><topic>Drug Resistance, Neoplasm</topic><topic>ErbB Receptors</topic><topic>Humans</topic><topic>Lung Neoplasms - drug therapy</topic><topic>Molecular Docking Simulation</topic><topic>Mutation</topic><topic>Protein Kinase Inhibitors - chemistry</topic><topic>Pyrimidines - chemistry</topic><topic>Tyrosine Kinase Inhibitors</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Mao, Yu-Ze</creatorcontrib><creatorcontrib>Xi, Xiao-Xiao</creatorcontrib><creatorcontrib>Zhao, Hong-Yi</creatorcontrib><creatorcontrib>Zhang, Yin-Liang</creatorcontrib><creatorcontrib>Zhang, San-Qi</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><jtitle>Bioorganic & medicinal chemistry letters</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Mao, Yu-Ze</au><au>Xi, Xiao-Xiao</au><au>Zhao, Hong-Yi</au><au>Zhang, Yin-Liang</au><au>Zhang, San-Qi</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Design, synthesis and evaluation of new pyrimidine derivatives as EGFR C797S tyrosine kinase inhibitors</atitle><jtitle>Bioorganic & medicinal chemistry letters</jtitle><addtitle>Bioorg Med Chem Lett</addtitle><date>2023-07-15</date><risdate>2023</risdate><volume>91</volume><spage>129381</spage><pages>129381-</pages><eissn>1464-3405</eissn><abstract>The clinical use of epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) in the treatment of non-small cell lung cancer was limited by the drug resistance caused by EGFR
mutation. Therefore, in order to overcome the drug resistance, we designed and synthesized a series of 2-aminopyrimidine derivatives as EGFR
-TKIs. Among these compounds, compounds A5 and A13 showed significant anti-proliferative activity against the KC-0116 (EGFR
) cell line with high selectivity. A5 inhibited EGFR phosphorylation and induced apoptosis of KC-0116 cell, arrested KC-0116 cell at G2/M phase. Molecular docking results showed that A5 and brigatinib bind to EGFR in a similar pattern. In addition to forming two important hydrogen bonds with Met793 residue, A5 also formed a hydrogen bond with Lys745 residues, which may play an important role for the potent inhibitory activity against EGFR
. Based on these results, A5 turned out to be effective reversible EGFR
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| ispartof | Bioorganic & medicinal chemistry letters, 2023-07, Vol.91, p.129381 |
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| source | MEDLINE; Elsevier ScienceDirect Journals |
| subjects | Antineoplastic Agents - chemistry Carcinoma, Non-Small-Cell Lung - drug therapy Drug Resistance, Neoplasm ErbB Receptors Humans Lung Neoplasms - drug therapy Molecular Docking Simulation Mutation Protein Kinase Inhibitors - chemistry Pyrimidines - chemistry Tyrosine Kinase Inhibitors |
| title | Design, synthesis and evaluation of new pyrimidine derivatives as EGFR C797S tyrosine kinase inhibitors |
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