Discovery of Selective and Potent Macrocyclic CDK9 Inhibitors for the Treatment of Osimertinib-Resistant Non-Small-Cell Lung Cancer
Effectiveness of epidermal growth factor receptor (EGFR) inhibitors, including Osimertinib, for treating non-small-cell lung cancer (NSCLC) is limited due to the continuous emergence of drug resistance. Hence, it is urgent to develop new therapeutic approaches. CDK9, a key regulator of RNA transcrip...
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| Veröffentlicht in: | Journal of medicinal chemistry 2023-11, Vol.66 (22), p.15340-15361 |
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| creator | Wu, Tizhi Yu, Bin Xu, Yifan Du, Zekun Zhang, Zhiming Wang, Yuxiao Chen, Haoming Zhang, Li Ao Chen, Rui Ma, Feihai Gong, Weihong Yu, Sixian Qiu, Zhixia Wu, Hongxi Xu, Xi Wang, Jubo Li, Zhiyu Bian, Jinlei |
| description | Effectiveness of epidermal growth factor receptor (EGFR) inhibitors, including Osimertinib, for treating non-small-cell lung cancer (NSCLC) is limited due to the continuous emergence of drug resistance. Hence, it is urgent to develop new therapeutic approaches. CDK9, a key regulator of RNA transcription, has emerged as a promising target for the development of antitumor drugs due to its crucial role in modulating the levels of antiapoptotic protein Mcl-1. Herein, we present the synthesis, optimization, and evaluation of selective CDK9 inhibitors with a macrocyclic scaffold that effectively suppresses the growth of NSCLC cells. Notably, compound
, a potent CDK9 inhibitor (IC
= 3.20 nM) with good kinase selectivity, significantly inhibits cell proliferation and colony formation and induces apoptosis in Osimertinib-resistant H1975 cells. Furthermore,
demonstrates a significant suppression of tumor growth in six patient-derived organoids, including three organoids resistant to Osimertinib. Overall,
served as a promising macrocycle-based CDK9 inhibitor for treating Osimertinib-resistant NSCLC. |
| doi_str_mv | 10.1021/acs.jmedchem.3c01400 |
| format | Article |
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, a potent CDK9 inhibitor (IC
= 3.20 nM) with good kinase selectivity, significantly inhibits cell proliferation and colony formation and induces apoptosis in Osimertinib-resistant H1975 cells. Furthermore,
demonstrates a significant suppression of tumor growth in six patient-derived organoids, including three organoids resistant to Osimertinib. Overall,
served as a promising macrocycle-based CDK9 inhibitor for treating Osimertinib-resistant NSCLC.</description><identifier>ISSN: 0022-2623</identifier><identifier>EISSN: 1520-4804</identifier><identifier>DOI: 10.1021/acs.jmedchem.3c01400</identifier><identifier>PMID: 37870244</identifier><language>eng</language><publisher>United States</publisher><subject>Aniline Compounds - pharmacology ; Aniline Compounds - therapeutic use ; Carcinoma, Non-Small-Cell Lung - drug therapy ; Cell Line, Tumor ; Cyclin-Dependent Kinase 9 ; Drug Resistance, Neoplasm ; ErbB Receptors - metabolism ; Humans ; Lung Neoplasms - drug therapy ; Macrocyclic Compounds - pharmacology ; Macrocyclic Compounds - therapeutic use ; Mutation ; Protein Kinase Inhibitors - pharmacology ; Protein Kinase Inhibitors - therapeutic use</subject><ispartof>Journal of medicinal chemistry, 2023-11, Vol.66 (22), p.15340-15361</ispartof><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c307t-b0bead2707a8fd77a8e9a94f9518ba9f84be9bc4cc832ba96faac16e99fa232a3</citedby><cites>FETCH-LOGICAL-c307t-b0bead2707a8fd77a8e9a94f9518ba9f84be9bc4cc832ba96faac16e99fa232a3</cites><orcidid>0000-0001-6492-9511 ; 0000-0003-4552-1195</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,780,784,2765,27924,27925</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/37870244$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Wu, Tizhi</creatorcontrib><creatorcontrib>Yu, Bin</creatorcontrib><creatorcontrib>Xu, Yifan</creatorcontrib><creatorcontrib>Du, Zekun</creatorcontrib><creatorcontrib>Zhang, Zhiming</creatorcontrib><creatorcontrib>Wang, Yuxiao</creatorcontrib><creatorcontrib>Chen, Haoming</creatorcontrib><creatorcontrib>Zhang, Li Ao</creatorcontrib><creatorcontrib>Chen, Rui</creatorcontrib><creatorcontrib>Ma, Feihai</creatorcontrib><creatorcontrib>Gong, Weihong</creatorcontrib><creatorcontrib>Yu, Sixian</creatorcontrib><creatorcontrib>Qiu, Zhixia</creatorcontrib><creatorcontrib>Wu, Hongxi</creatorcontrib><creatorcontrib>Xu, Xi</creatorcontrib><creatorcontrib>Wang, Jubo</creatorcontrib><creatorcontrib>Li, Zhiyu</creatorcontrib><creatorcontrib>Bian, Jinlei</creatorcontrib><title>Discovery of Selective and Potent Macrocyclic CDK9 Inhibitors for the Treatment of Osimertinib-Resistant Non-Small-Cell Lung Cancer</title><title>Journal of medicinal chemistry</title><addtitle>J Med Chem</addtitle><description>Effectiveness of epidermal growth factor receptor (EGFR) inhibitors, including Osimertinib, for treating non-small-cell lung cancer (NSCLC) is limited due to the continuous emergence of drug resistance. Hence, it is urgent to develop new therapeutic approaches. CDK9, a key regulator of RNA transcription, has emerged as a promising target for the development of antitumor drugs due to its crucial role in modulating the levels of antiapoptotic protein Mcl-1. Herein, we present the synthesis, optimization, and evaluation of selective CDK9 inhibitors with a macrocyclic scaffold that effectively suppresses the growth of NSCLC cells. Notably, compound
, a potent CDK9 inhibitor (IC
= 3.20 nM) with good kinase selectivity, significantly inhibits cell proliferation and colony formation and induces apoptosis in Osimertinib-resistant H1975 cells. Furthermore,
demonstrates a significant suppression of tumor growth in six patient-derived organoids, including three organoids resistant to Osimertinib. Overall,
served as a promising macrocycle-based CDK9 inhibitor for treating Osimertinib-resistant NSCLC.</description><subject>Aniline Compounds - pharmacology</subject><subject>Aniline Compounds - therapeutic use</subject><subject>Carcinoma, Non-Small-Cell Lung - drug therapy</subject><subject>Cell Line, Tumor</subject><subject>Cyclin-Dependent Kinase 9</subject><subject>Drug Resistance, Neoplasm</subject><subject>ErbB Receptors - metabolism</subject><subject>Humans</subject><subject>Lung Neoplasms - drug therapy</subject><subject>Macrocyclic Compounds - pharmacology</subject><subject>Macrocyclic Compounds - therapeutic use</subject><subject>Mutation</subject><subject>Protein Kinase Inhibitors - pharmacology</subject><subject>Protein Kinase Inhibitors - therapeutic use</subject><issn>0022-2623</issn><issn>1520-4804</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2023</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNo9kE1PGzEQhq0KVFLaf1AhH7lsOv4g6z2ihbaooSCg59WsMyZGu2uwnUg594_XiNDLjDTvO18PY18FzAVI8Q1tmj-NtLJrGufKgtAAH9hMnEmotAF9wGYAUlZyIdUR-5TSEwAoIdVHdqRqU4PUesb-Xvhkw5bijgfH72kgm_2WOE4rfhsyTZlfo43B7uzgLW8vfjX8alr73ucQE3ch8rwm_hAJ8_jqLlNukh8pZj_5vrqj5FPGIvwOU3U_4jBULQ0DX26mR97iZCl-ZocOh0Rf9vmY_fl--dD-rJY3P67a82VlFdS56qEnXMkaajRuVZdIDTbaNWfC9Ng4o3tqequtNUqWwsIhWrGgpnEolUR1zE7f5j7H8LKhlLuxPF-OwYnCJnXSGDBSSgXFqt-s5fWUIrnuOfoR464T0L3i7wr-7h1_t8df2k72GzZ90f43vfNW_wARsYal</recordid><startdate>20231123</startdate><enddate>20231123</enddate><creator>Wu, Tizhi</creator><creator>Yu, Bin</creator><creator>Xu, Yifan</creator><creator>Du, Zekun</creator><creator>Zhang, Zhiming</creator><creator>Wang, Yuxiao</creator><creator>Chen, Haoming</creator><creator>Zhang, Li Ao</creator><creator>Chen, Rui</creator><creator>Ma, Feihai</creator><creator>Gong, Weihong</creator><creator>Yu, Sixian</creator><creator>Qiu, Zhixia</creator><creator>Wu, Hongxi</creator><creator>Xu, Xi</creator><creator>Wang, Jubo</creator><creator>Li, Zhiyu</creator><creator>Bian, Jinlei</creator><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/0000-0001-6492-9511</orcidid><orcidid>https://orcid.org/0000-0003-4552-1195</orcidid></search><sort><creationdate>20231123</creationdate><title>Discovery of Selective and Potent Macrocyclic CDK9 Inhibitors for the Treatment of Osimertinib-Resistant Non-Small-Cell Lung Cancer</title><author>Wu, Tizhi ; Yu, Bin ; Xu, Yifan ; Du, Zekun ; Zhang, Zhiming ; Wang, Yuxiao ; Chen, Haoming ; Zhang, Li Ao ; Chen, Rui ; Ma, Feihai ; Gong, Weihong ; Yu, Sixian ; Qiu, Zhixia ; Wu, Hongxi ; Xu, Xi ; Wang, Jubo ; Li, Zhiyu ; Bian, Jinlei</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c307t-b0bead2707a8fd77a8e9a94f9518ba9f84be9bc4cc832ba96faac16e99fa232a3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2023</creationdate><topic>Aniline Compounds - pharmacology</topic><topic>Aniline Compounds - therapeutic use</topic><topic>Carcinoma, Non-Small-Cell Lung - drug therapy</topic><topic>Cell Line, Tumor</topic><topic>Cyclin-Dependent Kinase 9</topic><topic>Drug Resistance, Neoplasm</topic><topic>ErbB Receptors - metabolism</topic><topic>Humans</topic><topic>Lung Neoplasms - drug therapy</topic><topic>Macrocyclic Compounds - pharmacology</topic><topic>Macrocyclic Compounds - therapeutic use</topic><topic>Mutation</topic><topic>Protein Kinase Inhibitors - pharmacology</topic><topic>Protein Kinase Inhibitors - therapeutic use</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Wu, Tizhi</creatorcontrib><creatorcontrib>Yu, Bin</creatorcontrib><creatorcontrib>Xu, Yifan</creatorcontrib><creatorcontrib>Du, Zekun</creatorcontrib><creatorcontrib>Zhang, Zhiming</creatorcontrib><creatorcontrib>Wang, Yuxiao</creatorcontrib><creatorcontrib>Chen, Haoming</creatorcontrib><creatorcontrib>Zhang, Li Ao</creatorcontrib><creatorcontrib>Chen, Rui</creatorcontrib><creatorcontrib>Ma, Feihai</creatorcontrib><creatorcontrib>Gong, Weihong</creatorcontrib><creatorcontrib>Yu, Sixian</creatorcontrib><creatorcontrib>Qiu, Zhixia</creatorcontrib><creatorcontrib>Wu, Hongxi</creatorcontrib><creatorcontrib>Xu, Xi</creatorcontrib><creatorcontrib>Wang, Jubo</creatorcontrib><creatorcontrib>Li, Zhiyu</creatorcontrib><creatorcontrib>Bian, Jinlei</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>Wu, Tizhi</au><au>Yu, Bin</au><au>Xu, Yifan</au><au>Du, Zekun</au><au>Zhang, Zhiming</au><au>Wang, Yuxiao</au><au>Chen, Haoming</au><au>Zhang, Li Ao</au><au>Chen, Rui</au><au>Ma, Feihai</au><au>Gong, Weihong</au><au>Yu, Sixian</au><au>Qiu, Zhixia</au><au>Wu, Hongxi</au><au>Xu, Xi</au><au>Wang, Jubo</au><au>Li, Zhiyu</au><au>Bian, Jinlei</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Discovery of Selective and Potent Macrocyclic CDK9 Inhibitors for the Treatment of Osimertinib-Resistant Non-Small-Cell Lung Cancer</atitle><jtitle>Journal of medicinal chemistry</jtitle><addtitle>J Med Chem</addtitle><date>2023-11-23</date><risdate>2023</risdate><volume>66</volume><issue>22</issue><spage>15340</spage><epage>15361</epage><pages>15340-15361</pages><issn>0022-2623</issn><eissn>1520-4804</eissn><abstract>Effectiveness of epidermal growth factor receptor (EGFR) inhibitors, including Osimertinib, for treating non-small-cell lung cancer (NSCLC) is limited due to the continuous emergence of drug resistance. Hence, it is urgent to develop new therapeutic approaches. CDK9, a key regulator of RNA transcription, has emerged as a promising target for the development of antitumor drugs due to its crucial role in modulating the levels of antiapoptotic protein Mcl-1. Herein, we present the synthesis, optimization, and evaluation of selective CDK9 inhibitors with a macrocyclic scaffold that effectively suppresses the growth of NSCLC cells. Notably, compound
, a potent CDK9 inhibitor (IC
= 3.20 nM) with good kinase selectivity, significantly inhibits cell proliferation and colony formation and induces apoptosis in Osimertinib-resistant H1975 cells. Furthermore,
demonstrates a significant suppression of tumor growth in six patient-derived organoids, including three organoids resistant to Osimertinib. Overall,
served as a promising macrocycle-based CDK9 inhibitor for treating Osimertinib-resistant NSCLC.</abstract><cop>United States</cop><pmid>37870244</pmid><doi>10.1021/acs.jmedchem.3c01400</doi><tpages>22</tpages><orcidid>https://orcid.org/0000-0001-6492-9511</orcidid><orcidid>https://orcid.org/0000-0003-4552-1195</orcidid></addata></record> |
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| ispartof | Journal of medicinal chemistry, 2023-11, Vol.66 (22), p.15340-15361 |
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| language | eng |
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| source | MEDLINE; American Chemical Society Journals |
| subjects | Aniline Compounds - pharmacology Aniline Compounds - therapeutic use Carcinoma, Non-Small-Cell Lung - drug therapy Cell Line, Tumor Cyclin-Dependent Kinase 9 Drug Resistance, Neoplasm ErbB Receptors - metabolism Humans Lung Neoplasms - drug therapy Macrocyclic Compounds - pharmacology Macrocyclic Compounds - therapeutic use Mutation Protein Kinase Inhibitors - pharmacology Protein Kinase Inhibitors - therapeutic use |
| title | Discovery of Selective and Potent Macrocyclic CDK9 Inhibitors for the Treatment of Osimertinib-Resistant Non-Small-Cell Lung Cancer |
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