Development of (2-(Benzyloxy)phenyl)methanamine Derivatives as Potent and Selective Inhibitors of CARM1 for the Treatment of Melanoma
Coactivator-associated arginine methyltransferase 1 (CARM1), an important member of type I protein arginine methyltransferases (PRMTs), has emerged as a promising therapeutic target for various cancer types. In our previous study, we have identified a series of type I PRMT inhibitors, among which ZL...
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| Veröffentlicht in: | Journal of medicinal chemistry 2024-04, Vol.67 (8), p.6313-6326 |
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| container_title | Journal of medicinal chemistry |
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| creator | Liu, Zhihao Lin, Min Liu, Chenyu Chen, Xin Chen, Qian Li, Xinyu Wu, Xiaoyan Wang, Yahui Wang, Lei Yang, Fan Luo, Cheng Jin, Jia Ye, Fei |
| description | Coactivator-associated arginine methyltransferase 1 (CARM1), an important member of type I protein arginine methyltransferases (PRMTs), has emerged as a promising therapeutic target for various cancer types. In our previous study, we have identified a series of type I PRMT inhibitors, among which ZL-28-6 (6) exhibited increased activity against CARM1 while displaying decreased potency against other type I PRMTs. In this work, we conducted chemical modifications on compound 6, resulting in a series of (2-(benzyloxy)phenyl)methanamine derivatives as potent inhibitors of CARM1. Among them, compound 17e displayed remarkable potency and selectivity for CARM1 (IC50 = 2 ± 1 nM), along with notable antiproliferative effects against melanoma cell lines. Cellular thermal shift assay and western blot experiments confirmed that compound 6 effectively targets CARM1 within cells. Furthermore, compound 17e displayed good antitumor efficacy in a melanoma xenograft model, indicating that this compound warrants further investigation as a potential anticancer agent. |
| doi_str_mv | 10.1021/acs.jmedchem.3c02265 |
| format | Article |
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In our previous study, we have identified a series of type I PRMT inhibitors, among which ZL-28-6 (6) exhibited increased activity against CARM1 while displaying decreased potency against other type I PRMTs. In this work, we conducted chemical modifications on compound 6, resulting in a series of (2-(benzyloxy)phenyl)methanamine derivatives as potent inhibitors of CARM1. Among them, compound 17e displayed remarkable potency and selectivity for CARM1 (IC50 = 2 ± 1 nM), along with notable antiproliferative effects against melanoma cell lines. Cellular thermal shift assay and western blot experiments confirmed that compound 6 effectively targets CARM1 within cells. Furthermore, compound 17e displayed good antitumor efficacy in a melanoma xenograft model, indicating that this compound warrants further investigation as a potential anticancer agent.</description><identifier>ISSN: 0022-2623</identifier><identifier>EISSN: 1520-4804</identifier><identifier>DOI: 10.1021/acs.jmedchem.3c02265</identifier><identifier>PMID: 38574345</identifier><language>eng</language><publisher>United States: American Chemical Society</publisher><subject>Animals ; Antineoplastic Agents - chemical synthesis ; Antineoplastic Agents - chemistry ; Antineoplastic Agents - pharmacology ; Antineoplastic Agents - therapeutic use ; Cell Line, Tumor ; Cell Proliferation - drug effects ; Drug Screening Assays, Antitumor ; Enzyme Inhibitors - chemical synthesis ; Enzyme Inhibitors - chemistry ; Enzyme Inhibitors - pharmacology ; Enzyme Inhibitors - therapeutic use ; Humans ; Melanoma - drug therapy ; Melanoma - pathology ; Mice ; Mice, Nude ; Protein-Arginine N-Methyltransferases - antagonists & inhibitors ; Protein-Arginine N-Methyltransferases - metabolism ; Structure-Activity Relationship ; Xenograft Model Antitumor Assays</subject><ispartof>Journal of medicinal chemistry, 2024-04, Vol.67 (8), p.6313-6326</ispartof><rights>2024 American Chemical Society</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-a348t-d4736a3a1b067e5246c9d3fd2b0c8a8ce23800a3d3a987b9a781973c400f7f643</citedby><cites>FETCH-LOGICAL-a348t-d4736a3a1b067e5246c9d3fd2b0c8a8ce23800a3d3a987b9a781973c400f7f643</cites><orcidid>0000-0003-4119-3219 ; 0000-0003-3315-4797 ; 0000-0003-3864-8382</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.3c02265$$EPDF$$P50$$Gacs$$H</linktopdf><linktohtml>$$Uhttps://pubs.acs.org/doi/10.1021/acs.jmedchem.3c02265$$EHTML$$P50$$Gacs$$H</linktohtml><link.rule.ids>314,780,784,2765,27076,27924,27925,56738,56788</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/38574345$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Liu, Zhihao</creatorcontrib><creatorcontrib>Lin, Min</creatorcontrib><creatorcontrib>Liu, Chenyu</creatorcontrib><creatorcontrib>Chen, Xin</creatorcontrib><creatorcontrib>Chen, Qian</creatorcontrib><creatorcontrib>Li, Xinyu</creatorcontrib><creatorcontrib>Wu, Xiaoyan</creatorcontrib><creatorcontrib>Wang, Yahui</creatorcontrib><creatorcontrib>Wang, Lei</creatorcontrib><creatorcontrib>Yang, Fan</creatorcontrib><creatorcontrib>Luo, Cheng</creatorcontrib><creatorcontrib>Jin, Jia</creatorcontrib><creatorcontrib>Ye, Fei</creatorcontrib><title>Development of (2-(Benzyloxy)phenyl)methanamine Derivatives as Potent and Selective Inhibitors of CARM1 for the Treatment of Melanoma</title><title>Journal of medicinal chemistry</title><addtitle>J. Med. Chem</addtitle><description>Coactivator-associated arginine methyltransferase 1 (CARM1), an important member of type I protein arginine methyltransferases (PRMTs), has emerged as a promising therapeutic target for various cancer types. In our previous study, we have identified a series of type I PRMT inhibitors, among which ZL-28-6 (6) exhibited increased activity against CARM1 while displaying decreased potency against other type I PRMTs. In this work, we conducted chemical modifications on compound 6, resulting in a series of (2-(benzyloxy)phenyl)methanamine derivatives as potent inhibitors of CARM1. Among them, compound 17e displayed remarkable potency and selectivity for CARM1 (IC50 = 2 ± 1 nM), along with notable antiproliferative effects against melanoma cell lines. Cellular thermal shift assay and western blot experiments confirmed that compound 6 effectively targets CARM1 within cells. Furthermore, compound 17e displayed good antitumor efficacy in a melanoma xenograft model, indicating that this compound warrants further investigation as a potential anticancer agent.</description><subject>Animals</subject><subject>Antineoplastic Agents - chemical synthesis</subject><subject>Antineoplastic Agents - chemistry</subject><subject>Antineoplastic Agents - pharmacology</subject><subject>Antineoplastic Agents - therapeutic use</subject><subject>Cell Line, Tumor</subject><subject>Cell Proliferation - drug effects</subject><subject>Drug Screening Assays, Antitumor</subject><subject>Enzyme Inhibitors - chemical synthesis</subject><subject>Enzyme Inhibitors - chemistry</subject><subject>Enzyme Inhibitors - pharmacology</subject><subject>Enzyme Inhibitors - therapeutic use</subject><subject>Humans</subject><subject>Melanoma - drug therapy</subject><subject>Melanoma - pathology</subject><subject>Mice</subject><subject>Mice, Nude</subject><subject>Protein-Arginine N-Methyltransferases - antagonists & inhibitors</subject><subject>Protein-Arginine N-Methyltransferases - metabolism</subject><subject>Structure-Activity Relationship</subject><subject>Xenograft Model Antitumor Assays</subject><issn>0022-2623</issn><issn>1520-4804</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2024</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp9UUtP20AQXiFQCbT_AFV7DAensw8_coRQWiRQqwJna7wey0b2brq7iRru_O86TdIjp5FmvsfMfIxdCJgJkOILmjB7Gag2LQ0zZUDKLD1iE5FKSHQB-phNYGwmMpPqlJ2F8AIASkj1gZ2qIs210umEvd3Qmnq3HMhG7ho-lcn0muzrpnd_NpfLluymvxwotmhx6CzxG_LdGmO3psAx8J8ubploa_5IPZntgN_Ztqu66HzYSi6ufj0I3jjPY0v8yRPGg9sD9WjdgB_ZSYN9oE_7es6eb78-Lb4n9z--3S2u7hNUuohJrXOVoUJRQZZTKnVm5rVqalmBKbAwJFUBgKpWOC_yao55Iea5MhqgyZtMq3M23ekuvfu9ohDLoQuG-nELcqtQKlBaaplnMEL1Dmq8C8FTUy59N6DflALKbQDlGEB5CKDcBzDSPu8dVtU4-086fHwEwA7wj-5W3o4Hv6_5F2VwlbQ</recordid><startdate>20240425</startdate><enddate>20240425</enddate><creator>Liu, Zhihao</creator><creator>Lin, Min</creator><creator>Liu, Chenyu</creator><creator>Chen, Xin</creator><creator>Chen, Qian</creator><creator>Li, Xinyu</creator><creator>Wu, Xiaoyan</creator><creator>Wang, Yahui</creator><creator>Wang, Lei</creator><creator>Yang, Fan</creator><creator>Luo, Cheng</creator><creator>Jin, Jia</creator><creator>Ye, Fei</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/0000-0003-4119-3219</orcidid><orcidid>https://orcid.org/0000-0003-3315-4797</orcidid><orcidid>https://orcid.org/0000-0003-3864-8382</orcidid></search><sort><creationdate>20240425</creationdate><title>Development of (2-(Benzyloxy)phenyl)methanamine Derivatives as Potent and Selective Inhibitors of CARM1 for the Treatment of Melanoma</title><author>Liu, Zhihao ; Lin, Min ; Liu, Chenyu ; Chen, Xin ; Chen, Qian ; Li, Xinyu ; Wu, Xiaoyan ; Wang, Yahui ; Wang, Lei ; Yang, Fan ; Luo, Cheng ; Jin, Jia ; Ye, Fei</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-a348t-d4736a3a1b067e5246c9d3fd2b0c8a8ce23800a3d3a987b9a781973c400f7f643</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2024</creationdate><topic>Animals</topic><topic>Antineoplastic Agents - chemical synthesis</topic><topic>Antineoplastic Agents - chemistry</topic><topic>Antineoplastic Agents - pharmacology</topic><topic>Antineoplastic Agents - therapeutic use</topic><topic>Cell Line, Tumor</topic><topic>Cell Proliferation - drug effects</topic><topic>Drug Screening Assays, Antitumor</topic><topic>Enzyme Inhibitors - chemical synthesis</topic><topic>Enzyme Inhibitors - chemistry</topic><topic>Enzyme Inhibitors - pharmacology</topic><topic>Enzyme Inhibitors - therapeutic use</topic><topic>Humans</topic><topic>Melanoma - drug therapy</topic><topic>Melanoma - pathology</topic><topic>Mice</topic><topic>Mice, Nude</topic><topic>Protein-Arginine N-Methyltransferases - antagonists & inhibitors</topic><topic>Protein-Arginine N-Methyltransferases - metabolism</topic><topic>Structure-Activity Relationship</topic><topic>Xenograft Model Antitumor Assays</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Liu, Zhihao</creatorcontrib><creatorcontrib>Lin, Min</creatorcontrib><creatorcontrib>Liu, Chenyu</creatorcontrib><creatorcontrib>Chen, Xin</creatorcontrib><creatorcontrib>Chen, Qian</creatorcontrib><creatorcontrib>Li, Xinyu</creatorcontrib><creatorcontrib>Wu, Xiaoyan</creatorcontrib><creatorcontrib>Wang, Yahui</creatorcontrib><creatorcontrib>Wang, Lei</creatorcontrib><creatorcontrib>Yang, Fan</creatorcontrib><creatorcontrib>Luo, Cheng</creatorcontrib><creatorcontrib>Jin, Jia</creatorcontrib><creatorcontrib>Ye, Fei</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>Liu, Zhihao</au><au>Lin, Min</au><au>Liu, Chenyu</au><au>Chen, Xin</au><au>Chen, Qian</au><au>Li, Xinyu</au><au>Wu, Xiaoyan</au><au>Wang, Yahui</au><au>Wang, Lei</au><au>Yang, Fan</au><au>Luo, Cheng</au><au>Jin, Jia</au><au>Ye, Fei</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Development of (2-(Benzyloxy)phenyl)methanamine Derivatives as Potent and Selective Inhibitors of CARM1 for the Treatment of Melanoma</atitle><jtitle>Journal of medicinal chemistry</jtitle><addtitle>J. Med. Chem</addtitle><date>2024-04-25</date><risdate>2024</risdate><volume>67</volume><issue>8</issue><spage>6313</spage><epage>6326</epage><pages>6313-6326</pages><issn>0022-2623</issn><eissn>1520-4804</eissn><abstract>Coactivator-associated arginine methyltransferase 1 (CARM1), an important member of type I protein arginine methyltransferases (PRMTs), has emerged as a promising therapeutic target for various cancer types. In our previous study, we have identified a series of type I PRMT inhibitors, among which ZL-28-6 (6) exhibited increased activity against CARM1 while displaying decreased potency against other type I PRMTs. In this work, we conducted chemical modifications on compound 6, resulting in a series of (2-(benzyloxy)phenyl)methanamine derivatives as potent inhibitors of CARM1. Among them, compound 17e displayed remarkable potency and selectivity for CARM1 (IC50 = 2 ± 1 nM), along with notable antiproliferative effects against melanoma cell lines. Cellular thermal shift assay and western blot experiments confirmed that compound 6 effectively targets CARM1 within cells. Furthermore, compound 17e displayed good antitumor efficacy in a melanoma xenograft model, indicating that this compound warrants further investigation as a potential anticancer agent.</abstract><cop>United States</cop><pub>American Chemical Society</pub><pmid>38574345</pmid><doi>10.1021/acs.jmedchem.3c02265</doi><tpages>14</tpages><orcidid>https://orcid.org/0000-0003-4119-3219</orcidid><orcidid>https://orcid.org/0000-0003-3315-4797</orcidid><orcidid>https://orcid.org/0000-0003-3864-8382</orcidid></addata></record> |
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| subjects | Animals Antineoplastic Agents - chemical synthesis Antineoplastic Agents - chemistry Antineoplastic Agents - pharmacology Antineoplastic Agents - therapeutic use Cell Line, Tumor Cell Proliferation - drug effects Drug Screening Assays, Antitumor Enzyme Inhibitors - chemical synthesis Enzyme Inhibitors - chemistry Enzyme Inhibitors - pharmacology Enzyme Inhibitors - therapeutic use Humans Melanoma - drug therapy Melanoma - pathology Mice Mice, Nude Protein-Arginine N-Methyltransferases - antagonists & inhibitors Protein-Arginine N-Methyltransferases - metabolism Structure-Activity Relationship Xenograft Model Antitumor Assays |
| title | Development of (2-(Benzyloxy)phenyl)methanamine Derivatives as Potent and Selective Inhibitors of CARM1 for the Treatment of Melanoma |
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