Conformational Constrained 4‑(1-Sulfonyl-3-indol)yl-2-phenylaminopyrimidine Derivatives as New Fourth-Generation Epidermal Growth Factor Receptor Inhibitors Targeting T790M/C797S Mutations
Tertiary C797S mutation of epidermal growth factor receptor (EGFR)-mediated resistance in non-small-cell-lung-cancer (NSCLC) patients is still an unmet clinical need. Several classes of adenosine 5′-triphosphate-competitive or allosteric EGFRT790M/C797S inhibitors and degraders have been developed,...
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| Veröffentlicht in: | Journal of medicinal chemistry 2022-05, Vol.65 (9), p.6840-6858 |
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| container_title | Journal of medicinal chemistry |
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| creator | Chen, Hao Lai, Mengzhen Zhang, Tao Chen, Yuqing Tong, Linjiang Zhu, Sujie Zhou, Yang Ren, Xiaomei Ding, Jian Xie, Hua Lu, Xiaoyun Ding, Ke |
| description | Tertiary C797S mutation of epidermal growth factor receptor (EGFR)-mediated resistance in non-small-cell-lung-cancer (NSCLC) patients is still an unmet clinical need. Several classes of adenosine 5′-triphosphate-competitive or allosteric EGFRT790M/C797S inhibitors and degraders have been developed, but none of them have received approval from the regulatory agencies. Herein, we report the structure-based design of conformational constrained 4-(1-ethylsufonyl-3-indolyl)-2-phenylaminopyrimidines as new EGFRT790M/C797S inhibitors by using a macrocyclization strategy. Representative compound 18j potently inhibited EGFR19del/T790M/C797S and EGFRL858R/T790M/C797S mutants with IC50 values of 15.8 and 23.6 nM and suppressed Ba/F3-EGFRL858R/T790M/C797S and Ba/F3-EGFR19del/T790M/C797S cells with IC50 values of 0.036 and 0.052 μM, respectively, which is 10–20-fold more potent than brigatinib. 18j also potently inhibited the EGFR19del/T790M/C797S-mutated PC-9-OR NSCLC cell proliferation with an IC50 value of 0.644 μM but was less potent for parental Ba/F3 and A431 cells. This study provides a new lead compound for drug discovery to combat EGFRC797S-mediated resistance in NSCLC patients. |
| doi_str_mv | 10.1021/acs.jmedchem.2c00168 |
| format | Article |
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Several classes of adenosine 5′-triphosphate-competitive or allosteric EGFRT790M/C797S inhibitors and degraders have been developed, but none of them have received approval from the regulatory agencies. Herein, we report the structure-based design of conformational constrained 4-(1-ethylsufonyl-3-indolyl)-2-phenylaminopyrimidines as new EGFRT790M/C797S inhibitors by using a macrocyclization strategy. Representative compound 18j potently inhibited EGFR19del/T790M/C797S and EGFRL858R/T790M/C797S mutants with IC50 values of 15.8 and 23.6 nM and suppressed Ba/F3-EGFRL858R/T790M/C797S and Ba/F3-EGFR19del/T790M/C797S cells with IC50 values of 0.036 and 0.052 μM, respectively, which is 10–20-fold more potent than brigatinib. 18j also potently inhibited the EGFR19del/T790M/C797S-mutated PC-9-OR NSCLC cell proliferation with an IC50 value of 0.644 μM but was less potent for parental Ba/F3 and A431 cells. This study provides a new lead compound for drug discovery to combat EGFRC797S-mediated resistance in NSCLC patients.</description><identifier>ISSN: 0022-2623</identifier><identifier>EISSN: 1520-4804</identifier><identifier>DOI: 10.1021/acs.jmedchem.2c00168</identifier><identifier>PMID: 35446588</identifier><language>eng</language><publisher>United States: American Chemical Society</publisher><subject>Carcinoma, Non-Small-Cell Lung - drug therapy ; Carcinoma, Non-Small-Cell Lung - genetics ; Drug Resistance, Neoplasm ; ErbB Receptors ; Humans ; Lung Neoplasms - drug therapy ; Lung Neoplasms - genetics ; Mutation ; Protein Kinase Inhibitors - pharmacology</subject><ispartof>Journal of medicinal chemistry, 2022-05, Vol.65 (9), p.6840-6858</ispartof><rights>2022 American Chemical Society</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-a263t-e76540eba249dec877ae8627b1c89a93cbaf9fb6f8d4e85222c840cf5c0778b93</citedby><cites>FETCH-LOGICAL-a263t-e76540eba249dec877ae8627b1c89a93cbaf9fb6f8d4e85222c840cf5c0778b93</cites><orcidid>0000-0001-7931-6873 ; 0000-0003-4167-6413 ; 0000-0001-9016-812X</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://pubs.acs.org/doi/pdf/10.1021/acs.jmedchem.2c00168$$EPDF$$P50$$Gacs$$H</linktopdf><linktohtml>$$Uhttps://pubs.acs.org/doi/10.1021/acs.jmedchem.2c00168$$EHTML$$P50$$Gacs$$H</linktohtml><link.rule.ids>314,780,784,2764,27075,27923,27924,56737,56787</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/35446588$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Chen, Hao</creatorcontrib><creatorcontrib>Lai, Mengzhen</creatorcontrib><creatorcontrib>Zhang, Tao</creatorcontrib><creatorcontrib>Chen, Yuqing</creatorcontrib><creatorcontrib>Tong, Linjiang</creatorcontrib><creatorcontrib>Zhu, Sujie</creatorcontrib><creatorcontrib>Zhou, Yang</creatorcontrib><creatorcontrib>Ren, Xiaomei</creatorcontrib><creatorcontrib>Ding, Jian</creatorcontrib><creatorcontrib>Xie, Hua</creatorcontrib><creatorcontrib>Lu, Xiaoyun</creatorcontrib><creatorcontrib>Ding, Ke</creatorcontrib><title>Conformational Constrained 4‑(1-Sulfonyl-3-indol)yl-2-phenylaminopyrimidine Derivatives as New Fourth-Generation Epidermal Growth Factor Receptor Inhibitors Targeting T790M/C797S Mutations</title><title>Journal of medicinal chemistry</title><addtitle>J. Med. Chem</addtitle><description>Tertiary C797S mutation of epidermal growth factor receptor (EGFR)-mediated resistance in non-small-cell-lung-cancer (NSCLC) patients is still an unmet clinical need. Several classes of adenosine 5′-triphosphate-competitive or allosteric EGFRT790M/C797S inhibitors and degraders have been developed, but none of them have received approval from the regulatory agencies. Herein, we report the structure-based design of conformational constrained 4-(1-ethylsufonyl-3-indolyl)-2-phenylaminopyrimidines as new EGFRT790M/C797S inhibitors by using a macrocyclization strategy. Representative compound 18j potently inhibited EGFR19del/T790M/C797S and EGFRL858R/T790M/C797S mutants with IC50 values of 15.8 and 23.6 nM and suppressed Ba/F3-EGFRL858R/T790M/C797S and Ba/F3-EGFR19del/T790M/C797S cells with IC50 values of 0.036 and 0.052 μM, respectively, which is 10–20-fold more potent than brigatinib. 18j also potently inhibited the EGFR19del/T790M/C797S-mutated PC-9-OR NSCLC cell proliferation with an IC50 value of 0.644 μM but was less potent for parental Ba/F3 and A431 cells. This study provides a new lead compound for drug discovery to combat EGFRC797S-mediated resistance in NSCLC patients.</description><subject>Carcinoma, Non-Small-Cell Lung - drug therapy</subject><subject>Carcinoma, Non-Small-Cell Lung - genetics</subject><subject>Drug Resistance, Neoplasm</subject><subject>ErbB Receptors</subject><subject>Humans</subject><subject>Lung Neoplasms - drug therapy</subject><subject>Lung Neoplasms - genetics</subject><subject>Mutation</subject><subject>Protein Kinase Inhibitors - pharmacology</subject><issn>0022-2623</issn><issn>1520-4804</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2022</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp9UU1u1DAYtRCIDoUbIORlWXjqOE7sLNG0M1RqQaLDOnKcL42rxA6202p2XIELcRhOgjszZcnKz_b7kd5D6H1Glxll2bnSYXk_Qqt7GJdMU5qV8gVaZAWjhEvKX6IFpYwRVrL8BL0J4Z5Smmcsf41O8oLzspBygX6vnO2cH1U0zqoBp2uIXhkLLeZ_fv46y8jtPHTO7gaSE2NbN3xMkJGph_SmRmPdtPNmNG3S4Avw5iF5PUDAKuAv8IjXbvaxJxuw4Pcp-HIyLaTIAW-8e4w9XisdncffQMP0BK5sbxqTUMBb5e8gGnuHt6KiN-crUYlbfDPHvVV4i151agjw7nieou_ry-3qM7n-urlafbomipV5JCDKglNoFONVC1oKoUCWTDSZlpWqct2oruqaspMtB1kwxrTkVHeFpkLIpspP0dnBd_Luxwwh1qMJGoZBWXBzqFnyZ5Kn8hOVH6jauxA8dPWU6lF-V2e0flquTsvVz8vVx-WS7MMxYW7S3z_R81SJQA-EvTyVmuYK__f8C71urLw</recordid><startdate>20220512</startdate><enddate>20220512</enddate><creator>Chen, Hao</creator><creator>Lai, Mengzhen</creator><creator>Zhang, Tao</creator><creator>Chen, Yuqing</creator><creator>Tong, Linjiang</creator><creator>Zhu, Sujie</creator><creator>Zhou, Yang</creator><creator>Ren, Xiaomei</creator><creator>Ding, Jian</creator><creator>Xie, Hua</creator><creator>Lu, Xiaoyun</creator><creator>Ding, Ke</creator><general>American Chemical Society</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope><orcidid>https://orcid.org/0000-0001-7931-6873</orcidid><orcidid>https://orcid.org/0000-0003-4167-6413</orcidid><orcidid>https://orcid.org/0000-0001-9016-812X</orcidid></search><sort><creationdate>20220512</creationdate><title>Conformational Constrained 4‑(1-Sulfonyl-3-indol)yl-2-phenylaminopyrimidine Derivatives as New Fourth-Generation Epidermal Growth Factor Receptor Inhibitors Targeting T790M/C797S Mutations</title><author>Chen, Hao ; Lai, Mengzhen ; Zhang, Tao ; Chen, Yuqing ; Tong, Linjiang ; Zhu, Sujie ; Zhou, Yang ; Ren, Xiaomei ; Ding, Jian ; Xie, Hua ; Lu, Xiaoyun ; Ding, Ke</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-a263t-e76540eba249dec877ae8627b1c89a93cbaf9fb6f8d4e85222c840cf5c0778b93</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2022</creationdate><topic>Carcinoma, Non-Small-Cell Lung - drug therapy</topic><topic>Carcinoma, Non-Small-Cell Lung - genetics</topic><topic>Drug Resistance, Neoplasm</topic><topic>ErbB Receptors</topic><topic>Humans</topic><topic>Lung Neoplasms - drug therapy</topic><topic>Lung Neoplasms - genetics</topic><topic>Mutation</topic><topic>Protein Kinase Inhibitors - pharmacology</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Chen, Hao</creatorcontrib><creatorcontrib>Lai, Mengzhen</creatorcontrib><creatorcontrib>Zhang, Tao</creatorcontrib><creatorcontrib>Chen, Yuqing</creatorcontrib><creatorcontrib>Tong, Linjiang</creatorcontrib><creatorcontrib>Zhu, Sujie</creatorcontrib><creatorcontrib>Zhou, Yang</creatorcontrib><creatorcontrib>Ren, Xiaomei</creatorcontrib><creatorcontrib>Ding, Jian</creatorcontrib><creatorcontrib>Xie, Hua</creatorcontrib><creatorcontrib>Lu, Xiaoyun</creatorcontrib><creatorcontrib>Ding, Ke</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><jtitle>Journal of medicinal chemistry</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Chen, Hao</au><au>Lai, Mengzhen</au><au>Zhang, Tao</au><au>Chen, Yuqing</au><au>Tong, Linjiang</au><au>Zhu, Sujie</au><au>Zhou, Yang</au><au>Ren, Xiaomei</au><au>Ding, Jian</au><au>Xie, Hua</au><au>Lu, Xiaoyun</au><au>Ding, Ke</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Conformational Constrained 4‑(1-Sulfonyl-3-indol)yl-2-phenylaminopyrimidine Derivatives as New Fourth-Generation Epidermal Growth Factor Receptor Inhibitors Targeting T790M/C797S Mutations</atitle><jtitle>Journal of medicinal chemistry</jtitle><addtitle>J. Med. Chem</addtitle><date>2022-05-12</date><risdate>2022</risdate><volume>65</volume><issue>9</issue><spage>6840</spage><epage>6858</epage><pages>6840-6858</pages><issn>0022-2623</issn><eissn>1520-4804</eissn><abstract>Tertiary C797S mutation of epidermal growth factor receptor (EGFR)-mediated resistance in non-small-cell-lung-cancer (NSCLC) patients is still an unmet clinical need. Several classes of adenosine 5′-triphosphate-competitive or allosteric EGFRT790M/C797S inhibitors and degraders have been developed, but none of them have received approval from the regulatory agencies. Herein, we report the structure-based design of conformational constrained 4-(1-ethylsufonyl-3-indolyl)-2-phenylaminopyrimidines as new EGFRT790M/C797S inhibitors by using a macrocyclization strategy. Representative compound 18j potently inhibited EGFR19del/T790M/C797S and EGFRL858R/T790M/C797S mutants with IC50 values of 15.8 and 23.6 nM and suppressed Ba/F3-EGFRL858R/T790M/C797S and Ba/F3-EGFR19del/T790M/C797S cells with IC50 values of 0.036 and 0.052 μM, respectively, which is 10–20-fold more potent than brigatinib. 18j also potently inhibited the EGFR19del/T790M/C797S-mutated PC-9-OR NSCLC cell proliferation with an IC50 value of 0.644 μM but was less potent for parental Ba/F3 and A431 cells. This study provides a new lead compound for drug discovery to combat EGFRC797S-mediated resistance in NSCLC patients.</abstract><cop>United States</cop><pub>American Chemical Society</pub><pmid>35446588</pmid><doi>10.1021/acs.jmedchem.2c00168</doi><tpages>19</tpages><orcidid>https://orcid.org/0000-0001-7931-6873</orcidid><orcidid>https://orcid.org/0000-0003-4167-6413</orcidid><orcidid>https://orcid.org/0000-0001-9016-812X</orcidid></addata></record> |
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| subjects | Carcinoma, Non-Small-Cell Lung - drug therapy Carcinoma, Non-Small-Cell Lung - genetics Drug Resistance, Neoplasm ErbB Receptors Humans Lung Neoplasms - drug therapy Lung Neoplasms - genetics Mutation Protein Kinase Inhibitors - pharmacology |
| title | Conformational Constrained 4‑(1-Sulfonyl-3-indol)yl-2-phenylaminopyrimidine Derivatives as New Fourth-Generation Epidermal Growth Factor Receptor Inhibitors Targeting T790M/C797S Mutations |
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