Discovery of a 6-(pyridin-3-yl)benzo[d]thiazole template for optimization of hedgehog and PI3K/AKT/mTOR dual inhibitors
Vismodegib is the first FDA approved cancer therapy based on inhibition of aberrant hedgehog signaling. Like most cancer therapies, vismodegib suffered from resistance, even during clinical development. Numerous reports demonstrated that simultaneous blockage of hedgehog and PI3K/AKT/mTOR pathways r...
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| Veröffentlicht in: | Bioorganic & medicinal chemistry letters 2015-09, Vol.25 (17), p.3665-3670 |
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| creator | Yang, Zhaohui Ma, Haikuo Sun, Zhijian Luo, Lusong Tian, Sheng Zheng, Jiyue Zhang, Xiaohu |
| description | Vismodegib is the first FDA approved cancer therapy based on inhibition of aberrant hedgehog signaling. Like most cancer therapies, vismodegib suffered from resistance, even during clinical development. Numerous reports demonstrated that simultaneous blockage of hedgehog and PI3K/AKT/mTOR pathways resulted in significantly superior outcomes compared with single agent alone in a number of animal disease models. The dual hedgehog and PI3K/AKT/mTOR inhibition represented a promising approach not only to overcoming the resistance but also to delaying its onset. Here we report a series of compounds based on a 6-(pyridin-3-yl)benzo[d]thiazole template which have demonstrated significant inhibition of both hedgehog and PI3K/AKT/mTOR signaling pathways. This new scaffold can serve as a lead for further optimization. [Display omitted]
Vismodegib is the first FDA approved cancer therapy based on inhibition of aberrant hedgehog signaling. Like most cancer therapies, vismodegib suffered from resistance, even during clinical development. Numerous reports demonstrated that simultaneous blockage of hedgehog and PI3K/AKT/mTOR pathways resulted in significantly superior outcomes compared with single agent alone in a number of animal disease models. The dual hedgehog and PI3K/AKT/mTOR inhibition represented a promising approach not only to overcoming the resistance but also to delaying its onset. Here we report a series of compounds based on a 6-(pyridin-3-yl)benzo[d]thiazole template which have demonstrated significant inhibition of both hedgehog and PI3K/AKT/mTOR signaling pathways. This new scaffold can serve as a lead for further optimization. |
| doi_str_mv | 10.1016/j.bmcl.2015.06.049 |
| format | Article |
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Vismodegib is the first FDA approved cancer therapy based on inhibition of aberrant hedgehog signaling. Like most cancer therapies, vismodegib suffered from resistance, even during clinical development. Numerous reports demonstrated that simultaneous blockage of hedgehog and PI3K/AKT/mTOR pathways resulted in significantly superior outcomes compared with single agent alone in a number of animal disease models. The dual hedgehog and PI3K/AKT/mTOR inhibition represented a promising approach not only to overcoming the resistance but also to delaying its onset. Here we report a series of compounds based on a 6-(pyridin-3-yl)benzo[d]thiazole template which have demonstrated significant inhibition of both hedgehog and PI3K/AKT/mTOR signaling pathways. This new scaffold can serve as a lead for further optimization.</description><identifier>ISSN: 0960-894X</identifier><identifier>EISSN: 1464-3405</identifier><identifier>DOI: 10.1016/j.bmcl.2015.06.049</identifier><identifier>PMID: 26119500</identifier><language>eng</language><publisher>England: Elsevier Ltd</publisher><subject>Anilides - chemistry ; Anilides - pharmacology ; Animals ; Antineoplastic Agents - chemical synthesis ; Antineoplastic Agents - chemistry ; Antineoplastic Agents - pharmacology ; Cancer therapy ; Drug Design ; Drug Discovery ; Drug Screening Assays, Antitumor - methods ; GPCR ; Hedgehog pathway ; Hedgehog Proteins - antagonists & inhibitors ; Humans ; Kinase ; Mice ; Molecular Targeted Therapy - methods ; NIH 3T3 Cells - drug effects ; Phosphatidylinositol 3-Kinases - antagonists & inhibitors ; PI3K/AKT/mTOR pathway ; Polypharmacology ; Proto-Oncogene Proteins c-akt - antagonists & inhibitors ; Pyridines - chemistry ; Pyridines - pharmacology ; Structure-Activity Relationship ; Thiazoles - chemistry ; TOR Serine-Threonine Kinases - antagonists & inhibitors</subject><ispartof>Bioorganic & medicinal chemistry letters, 2015-09, Vol.25 (17), p.3665-3670</ispartof><rights>2015 Elsevier Ltd</rights><rights>Copyright © 2015 Elsevier Ltd. All rights reserved.</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c426t-74fb761f915476327fde15a190de95e275196f0a3660862e76aaa459727fd2fe3</citedby><cites>FETCH-LOGICAL-c426t-74fb761f915476327fde15a190de95e275196f0a3660862e76aaa459727fd2fe3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://www.sciencedirect.com/science/article/pii/S0960894X15006423$$EHTML$$P50$$Gelsevier$$H</linktohtml><link.rule.ids>314,776,780,3537,27901,27902,65306</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/26119500$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Yang, Zhaohui</creatorcontrib><creatorcontrib>Ma, Haikuo</creatorcontrib><creatorcontrib>Sun, Zhijian</creatorcontrib><creatorcontrib>Luo, Lusong</creatorcontrib><creatorcontrib>Tian, Sheng</creatorcontrib><creatorcontrib>Zheng, Jiyue</creatorcontrib><creatorcontrib>Zhang, Xiaohu</creatorcontrib><title>Discovery of a 6-(pyridin-3-yl)benzo[d]thiazole template for optimization of hedgehog and PI3K/AKT/mTOR dual inhibitors</title><title>Bioorganic & medicinal chemistry letters</title><addtitle>Bioorg Med Chem Lett</addtitle><description>Vismodegib is the first FDA approved cancer therapy based on inhibition of aberrant hedgehog signaling. Like most cancer therapies, vismodegib suffered from resistance, even during clinical development. Numerous reports demonstrated that simultaneous blockage of hedgehog and PI3K/AKT/mTOR pathways resulted in significantly superior outcomes compared with single agent alone in a number of animal disease models. The dual hedgehog and PI3K/AKT/mTOR inhibition represented a promising approach not only to overcoming the resistance but also to delaying its onset. Here we report a series of compounds based on a 6-(pyridin-3-yl)benzo[d]thiazole template which have demonstrated significant inhibition of both hedgehog and PI3K/AKT/mTOR signaling pathways. This new scaffold can serve as a lead for further optimization. [Display omitted]
Vismodegib is the first FDA approved cancer therapy based on inhibition of aberrant hedgehog signaling. Like most cancer therapies, vismodegib suffered from resistance, even during clinical development. Numerous reports demonstrated that simultaneous blockage of hedgehog and PI3K/AKT/mTOR pathways resulted in significantly superior outcomes compared with single agent alone in a number of animal disease models. The dual hedgehog and PI3K/AKT/mTOR inhibition represented a promising approach not only to overcoming the resistance but also to delaying its onset. Here we report a series of compounds based on a 6-(pyridin-3-yl)benzo[d]thiazole template which have demonstrated significant inhibition of both hedgehog and PI3K/AKT/mTOR signaling pathways. This new scaffold can serve as a lead for further optimization.</description><subject>Anilides - chemistry</subject><subject>Anilides - pharmacology</subject><subject>Animals</subject><subject>Antineoplastic Agents - chemical synthesis</subject><subject>Antineoplastic Agents - chemistry</subject><subject>Antineoplastic Agents - pharmacology</subject><subject>Cancer therapy</subject><subject>Drug Design</subject><subject>Drug Discovery</subject><subject>Drug Screening Assays, Antitumor - methods</subject><subject>GPCR</subject><subject>Hedgehog pathway</subject><subject>Hedgehog Proteins - antagonists & inhibitors</subject><subject>Humans</subject><subject>Kinase</subject><subject>Mice</subject><subject>Molecular Targeted Therapy - methods</subject><subject>NIH 3T3 Cells - drug effects</subject><subject>Phosphatidylinositol 3-Kinases - antagonists & inhibitors</subject><subject>PI3K/AKT/mTOR pathway</subject><subject>Polypharmacology</subject><subject>Proto-Oncogene Proteins c-akt - antagonists & inhibitors</subject><subject>Pyridines - chemistry</subject><subject>Pyridines - pharmacology</subject><subject>Structure-Activity Relationship</subject><subject>Thiazoles - chemistry</subject><subject>TOR Serine-Threonine Kinases - antagonists & inhibitors</subject><issn>0960-894X</issn><issn>1464-3405</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2015</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp9kMFu1DAURS1ERYfCD7BAXraLZJ4d25lIbKpSoGqlIjRISAhZTvzc8SiJg50pmvl6Ek3LktXdnHulewh5xyBnwNRym9dd0-YcmMxB5SCqF2TBhBJZIUC-JAuoFGSrSvw4Ja9T2gIwAUK8IqdcMVZJgAX589GnJjxi3NPgqKEqOx_20VvfZ0W2by9q7A_hp_01brw5hBbpiN3QmhGpC5GGYfSdP5jRh37ub9A-4CY8UNNb-vWmuF1e3q6X3fr-G7U701Lfb3ztxxDTG3LiTJvw7VOeke-frtdXX7K7-883V5d3WSO4GrNSuLpUzFVMilIVvHQWmTSsAouVRF5KVikHplAKVopjqYwxQlblTHKHxRk5P-4OMfzeYRp1Nx3GtjU9hl3SrARWsNVK8gnlR7SJIaWITg_RdybuNQM9C9dbPQvXs3ANSk_Cp9L7p_1d3aH9V3k2PAEfjgBOLx89Rp0aj32D1kdsRm2D_9_-X65skQM</recordid><startdate>20150901</startdate><enddate>20150901</enddate><creator>Yang, Zhaohui</creator><creator>Ma, Haikuo</creator><creator>Sun, Zhijian</creator><creator>Luo, Lusong</creator><creator>Tian, Sheng</creator><creator>Zheng, Jiyue</creator><creator>Zhang, Xiaohu</creator><general>Elsevier Ltd</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></search><sort><creationdate>20150901</creationdate><title>Discovery of a 6-(pyridin-3-yl)benzo[d]thiazole template for optimization of hedgehog and PI3K/AKT/mTOR dual inhibitors</title><author>Yang, Zhaohui ; Ma, Haikuo ; Sun, Zhijian ; Luo, Lusong ; Tian, Sheng ; Zheng, Jiyue ; Zhang, Xiaohu</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c426t-74fb761f915476327fde15a190de95e275196f0a3660862e76aaa459727fd2fe3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2015</creationdate><topic>Anilides - chemistry</topic><topic>Anilides - pharmacology</topic><topic>Animals</topic><topic>Antineoplastic Agents - chemical synthesis</topic><topic>Antineoplastic Agents - chemistry</topic><topic>Antineoplastic Agents - pharmacology</topic><topic>Cancer therapy</topic><topic>Drug Design</topic><topic>Drug Discovery</topic><topic>Drug Screening Assays, Antitumor - methods</topic><topic>GPCR</topic><topic>Hedgehog pathway</topic><topic>Hedgehog Proteins - antagonists & inhibitors</topic><topic>Humans</topic><topic>Kinase</topic><topic>Mice</topic><topic>Molecular Targeted Therapy - methods</topic><topic>NIH 3T3 Cells - drug effects</topic><topic>Phosphatidylinositol 3-Kinases - antagonists & inhibitors</topic><topic>PI3K/AKT/mTOR pathway</topic><topic>Polypharmacology</topic><topic>Proto-Oncogene Proteins c-akt - antagonists & inhibitors</topic><topic>Pyridines - chemistry</topic><topic>Pyridines - pharmacology</topic><topic>Structure-Activity Relationship</topic><topic>Thiazoles - chemistry</topic><topic>TOR Serine-Threonine Kinases - antagonists & inhibitors</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Yang, Zhaohui</creatorcontrib><creatorcontrib>Ma, Haikuo</creatorcontrib><creatorcontrib>Sun, Zhijian</creatorcontrib><creatorcontrib>Luo, Lusong</creatorcontrib><creatorcontrib>Tian, Sheng</creatorcontrib><creatorcontrib>Zheng, Jiyue</creatorcontrib><creatorcontrib>Zhang, Xiaohu</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>Bioorganic & medicinal chemistry letters</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Yang, Zhaohui</au><au>Ma, Haikuo</au><au>Sun, Zhijian</au><au>Luo, Lusong</au><au>Tian, Sheng</au><au>Zheng, Jiyue</au><au>Zhang, Xiaohu</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Discovery of a 6-(pyridin-3-yl)benzo[d]thiazole template for optimization of hedgehog and PI3K/AKT/mTOR dual inhibitors</atitle><jtitle>Bioorganic & medicinal chemistry letters</jtitle><addtitle>Bioorg Med Chem Lett</addtitle><date>2015-09-01</date><risdate>2015</risdate><volume>25</volume><issue>17</issue><spage>3665</spage><epage>3670</epage><pages>3665-3670</pages><issn>0960-894X</issn><eissn>1464-3405</eissn><abstract>Vismodegib is the first FDA approved cancer therapy based on inhibition of aberrant hedgehog signaling. Like most cancer therapies, vismodegib suffered from resistance, even during clinical development. Numerous reports demonstrated that simultaneous blockage of hedgehog and PI3K/AKT/mTOR pathways resulted in significantly superior outcomes compared with single agent alone in a number of animal disease models. The dual hedgehog and PI3K/AKT/mTOR inhibition represented a promising approach not only to overcoming the resistance but also to delaying its onset. Here we report a series of compounds based on a 6-(pyridin-3-yl)benzo[d]thiazole template which have demonstrated significant inhibition of both hedgehog and PI3K/AKT/mTOR signaling pathways. This new scaffold can serve as a lead for further optimization. [Display omitted]
Vismodegib is the first FDA approved cancer therapy based on inhibition of aberrant hedgehog signaling. Like most cancer therapies, vismodegib suffered from resistance, even during clinical development. Numerous reports demonstrated that simultaneous blockage of hedgehog and PI3K/AKT/mTOR pathways resulted in significantly superior outcomes compared with single agent alone in a number of animal disease models. The dual hedgehog and PI3K/AKT/mTOR inhibition represented a promising approach not only to overcoming the resistance but also to delaying its onset. Here we report a series of compounds based on a 6-(pyridin-3-yl)benzo[d]thiazole template which have demonstrated significant inhibition of both hedgehog and PI3K/AKT/mTOR signaling pathways. This new scaffold can serve as a lead for further optimization.</abstract><cop>England</cop><pub>Elsevier Ltd</pub><pmid>26119500</pmid><doi>10.1016/j.bmcl.2015.06.049</doi><tpages>6</tpages></addata></record> |
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| identifier | ISSN: 0960-894X |
| ispartof | Bioorganic & medicinal chemistry letters, 2015-09, Vol.25 (17), p.3665-3670 |
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| subjects | Anilides - chemistry Anilides - pharmacology Animals Antineoplastic Agents - chemical synthesis Antineoplastic Agents - chemistry Antineoplastic Agents - pharmacology Cancer therapy Drug Design Drug Discovery Drug Screening Assays, Antitumor - methods GPCR Hedgehog pathway Hedgehog Proteins - antagonists & inhibitors Humans Kinase Mice Molecular Targeted Therapy - methods NIH 3T3 Cells - drug effects Phosphatidylinositol 3-Kinases - antagonists & inhibitors PI3K/AKT/mTOR pathway Polypharmacology Proto-Oncogene Proteins c-akt - antagonists & inhibitors Pyridines - chemistry Pyridines - pharmacology Structure-Activity Relationship Thiazoles - chemistry TOR Serine-Threonine Kinases - antagonists & inhibitors |
| title | Discovery of a 6-(pyridin-3-yl)benzo[d]thiazole template for optimization of hedgehog and PI3K/AKT/mTOR dual inhibitors |
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