Development of Tumor-Targeting IRE-1 Inhibitors for B-cell Cancer Therapy
The IRE-1 kinase/RNase splices the mRNA of the XBP-1 gene, resulting in the spliced XBP-1 (XBP-1s) mRNA that encodes the functional XBP-1s transcription factor that is critically important for the growth and survival of B-cell leukemia, lymphoma, and multiple myeloma (MM). Several inhibitors targeti...
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Veröffentlicht in: | Molecular cancer therapeutics 2020-12, Vol.19 (12), p.2432-2444 |
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description | The IRE-1 kinase/RNase splices the mRNA of the XBP-1 gene, resulting in the spliced XBP-1 (XBP-1s) mRNA that encodes the functional XBP-1s transcription factor that is critically important for the growth and survival of B-cell leukemia, lymphoma, and multiple myeloma (MM). Several inhibitors targeting the expression of XBP-1s have been reported; however, the cytotoxicity exerted by each inhibitor against cancer cells is highly variable. To design better therapeutic strategies for B-cell cancer, we systematically compared the ability of these compounds to inhibit the RNase activity of IRE-1
and to suppress the expression of XBP-1s in mouse and human MM cell lines. Tricyclic chromenone-based inhibitors B-I09 and D-F07, prodrugs harboring an aldehyde-masking group, emerged as the most reliable inhibitors for potent suppression of XBP-1s expression in MM cells. The cytotoxicity of B-I09 and D-F07 against MM as well as chronic lymphocytic leukemia and mantle cell lymphoma could be further enhanced by combination with inhibitors of the PI3K/AKT pathway. Because chemical modifications of the salicylaldehyde hydroxy group could be used to tune 1,3-dioxane prodrug stability, we installed reactive oxygen species-sensitive structural cage groups onto these inhibitors to achieve stimuli-responsive activities and improve tumor-targeting efficiency. |
doi_str_mv | 10.1158/1535-7163.MCT-20-0127 |
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and to suppress the expression of XBP-1s in mouse and human MM cell lines. Tricyclic chromenone-based inhibitors B-I09 and D-F07, prodrugs harboring an aldehyde-masking group, emerged as the most reliable inhibitors for potent suppression of XBP-1s expression in MM cells. The cytotoxicity of B-I09 and D-F07 against MM as well as chronic lymphocytic leukemia and mantle cell lymphoma could be further enhanced by combination with inhibitors of the PI3K/AKT pathway. Because chemical modifications of the salicylaldehyde hydroxy group could be used to tune 1,3-dioxane prodrug stability, we installed reactive oxygen species-sensitive structural cage groups onto these inhibitors to achieve stimuli-responsive activities and improve tumor-targeting efficiency.</description><identifier>ISSN: 1535-7163</identifier><identifier>EISSN: 1538-8514</identifier><identifier>DOI: 10.1158/1535-7163.MCT-20-0127</identifier><identifier>PMID: 33051362</identifier><language>eng</language><publisher>United States</publisher><ispartof>Molecular cancer therapeutics, 2020-12, Vol.19 (12), p.2432-2444</ispartof><rights>2020 American Association for Cancer Research.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c411t-cec120edb1cf1d32b9618670380cf1f5ec71e20ab878e19882a6b49dd1bd54a33</citedby><cites>FETCH-LOGICAL-c411t-cec120edb1cf1d32b9618670380cf1f5ec71e20ab878e19882a6b49dd1bd54a33</cites><orcidid>0000-0002-6830-4567</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>230,314,776,780,881,3342,27903,27904</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/33051362$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Shao, Andong</creatorcontrib><creatorcontrib>Xu, Qin</creatorcontrib><creatorcontrib>Spalek, Walker T</creatorcontrib><creatorcontrib>Cain, Christopher F</creatorcontrib><creatorcontrib>Kang, Chang Won</creatorcontrib><creatorcontrib>Tang, Chih-Hang Anthony</creatorcontrib><creatorcontrib>Del Valle, Juan R</creatorcontrib><creatorcontrib>Hu, Chih-Chi Andrew</creatorcontrib><title>Development of Tumor-Targeting IRE-1 Inhibitors for B-cell Cancer Therapy</title><title>Molecular cancer therapeutics</title><addtitle>Mol Cancer Ther</addtitle><description>The IRE-1 kinase/RNase splices the mRNA of the XBP-1 gene, resulting in the spliced XBP-1 (XBP-1s) mRNA that encodes the functional XBP-1s transcription factor that is critically important for the growth and survival of B-cell leukemia, lymphoma, and multiple myeloma (MM). Several inhibitors targeting the expression of XBP-1s have been reported; however, the cytotoxicity exerted by each inhibitor against cancer cells is highly variable. To design better therapeutic strategies for B-cell cancer, we systematically compared the ability of these compounds to inhibit the RNase activity of IRE-1
and to suppress the expression of XBP-1s in mouse and human MM cell lines. Tricyclic chromenone-based inhibitors B-I09 and D-F07, prodrugs harboring an aldehyde-masking group, emerged as the most reliable inhibitors for potent suppression of XBP-1s expression in MM cells. The cytotoxicity of B-I09 and D-F07 against MM as well as chronic lymphocytic leukemia and mantle cell lymphoma could be further enhanced by combination with inhibitors of the PI3K/AKT pathway. Because chemical modifications of the salicylaldehyde hydroxy group could be used to tune 1,3-dioxane prodrug stability, we installed reactive oxygen species-sensitive structural cage groups onto these inhibitors to achieve stimuli-responsive activities and improve tumor-targeting efficiency.</description><issn>1535-7163</issn><issn>1538-8514</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2020</creationdate><recordtype>article</recordtype><recordid>eNpVUdFOgzAUbYzGzeknaHj0pbO3pVBeTBSnLpkxMfjcFCgbBii2sGR_Lzhd9One3J5z7u05CF0CmQNwcQOccRxCwOYvcYIpwQRoeISmw1xgwcE__u73mAk6c-6DEBARhVM0YYxwYAGdouWD3urKtLVuOs8UXtLXxuJE2bXuymbtLd8WGLxlsynTsjPWeYWx3j3OdFV5sWoybb1ko61qd-fopFCV0xc_dYbeHxdJ_IxXr0_L-G6FMx-gG5gZUKLzFLICckbTKAARhIQJMgwKrrMQNCUqFaHQEAlBVZD6UZ5DmnNfMTZDt3vdtk9rnWfD4VZVsrVlrexOGlXK_y9NuZFrs5VhGDIK_iBw_SNgzWevXSfr0o0fUo02vZPU5wAMeBAMUL6HZtY4Z3VxWANEjjHI0WI5WiyHGCQlcoxh4F39vfHA-vWdfQHiyIOx</recordid><startdate>20201201</startdate><enddate>20201201</enddate><creator>Shao, Andong</creator><creator>Xu, Qin</creator><creator>Spalek, Walker T</creator><creator>Cain, Christopher F</creator><creator>Kang, Chang Won</creator><creator>Tang, Chih-Hang Anthony</creator><creator>Del Valle, Juan R</creator><creator>Hu, Chih-Chi Andrew</creator><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope><scope>5PM</scope><orcidid>https://orcid.org/0000-0002-6830-4567</orcidid></search><sort><creationdate>20201201</creationdate><title>Development of Tumor-Targeting IRE-1 Inhibitors for B-cell Cancer Therapy</title><author>Shao, Andong ; Xu, Qin ; Spalek, Walker T ; Cain, Christopher F ; Kang, Chang Won ; Tang, Chih-Hang Anthony ; Del Valle, Juan R ; Hu, Chih-Chi Andrew</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c411t-cec120edb1cf1d32b9618670380cf1f5ec71e20ab878e19882a6b49dd1bd54a33</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2020</creationdate><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Shao, Andong</creatorcontrib><creatorcontrib>Xu, Qin</creatorcontrib><creatorcontrib>Spalek, Walker T</creatorcontrib><creatorcontrib>Cain, Christopher F</creatorcontrib><creatorcontrib>Kang, Chang Won</creatorcontrib><creatorcontrib>Tang, Chih-Hang Anthony</creatorcontrib><creatorcontrib>Del Valle, Juan R</creatorcontrib><creatorcontrib>Hu, Chih-Chi Andrew</creatorcontrib><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Molecular cancer therapeutics</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Shao, Andong</au><au>Xu, Qin</au><au>Spalek, Walker T</au><au>Cain, Christopher F</au><au>Kang, Chang Won</au><au>Tang, Chih-Hang Anthony</au><au>Del Valle, Juan R</au><au>Hu, Chih-Chi Andrew</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Development of Tumor-Targeting IRE-1 Inhibitors for B-cell Cancer Therapy</atitle><jtitle>Molecular cancer therapeutics</jtitle><addtitle>Mol Cancer Ther</addtitle><date>2020-12-01</date><risdate>2020</risdate><volume>19</volume><issue>12</issue><spage>2432</spage><epage>2444</epage><pages>2432-2444</pages><issn>1535-7163</issn><eissn>1538-8514</eissn><abstract>The IRE-1 kinase/RNase splices the mRNA of the XBP-1 gene, resulting in the spliced XBP-1 (XBP-1s) mRNA that encodes the functional XBP-1s transcription factor that is critically important for the growth and survival of B-cell leukemia, lymphoma, and multiple myeloma (MM). Several inhibitors targeting the expression of XBP-1s have been reported; however, the cytotoxicity exerted by each inhibitor against cancer cells is highly variable. To design better therapeutic strategies for B-cell cancer, we systematically compared the ability of these compounds to inhibit the RNase activity of IRE-1
and to suppress the expression of XBP-1s in mouse and human MM cell lines. Tricyclic chromenone-based inhibitors B-I09 and D-F07, prodrugs harboring an aldehyde-masking group, emerged as the most reliable inhibitors for potent suppression of XBP-1s expression in MM cells. The cytotoxicity of B-I09 and D-F07 against MM as well as chronic lymphocytic leukemia and mantle cell lymphoma could be further enhanced by combination with inhibitors of the PI3K/AKT pathway. Because chemical modifications of the salicylaldehyde hydroxy group could be used to tune 1,3-dioxane prodrug stability, we installed reactive oxygen species-sensitive structural cage groups onto these inhibitors to achieve stimuli-responsive activities and improve tumor-targeting efficiency.</abstract><cop>United States</cop><pmid>33051362</pmid><doi>10.1158/1535-7163.MCT-20-0127</doi><tpages>13</tpages><orcidid>https://orcid.org/0000-0002-6830-4567</orcidid><oa>free_for_read</oa></addata></record> |
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title | Development of Tumor-Targeting IRE-1 Inhibitors for B-cell Cancer Therapy |
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