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Lead Optimization of 2‑Phenylindolylglyoxylyldipeptide Murine Double Minute (MDM)2/Translocator Protein (TSPO) Dual Inhibitors for the Treatment of Gliomas
In glioblastoma multiforme (GBM), translocator protein (TSPO) and murine double minute (MDM)2/p53 complex represent two druggable targets. We recently reported the first dual binder 3 possessing a higher anticancer effect in GBM cells than the standards PK11195 1 or Nutlin-3 2 singularly applied. H...
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| Published in: | Journal of medicinal chemistry 2016-05, Vol.59 (10), p.4526-4538 |
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| Main Authors: | , , , , , , , , , , , , |
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| cited_by | cdi_FETCH-LOGICAL-a394t-320c324126bbfaa31762a529cf4e5ec0235e9c266acc96ff652eefc9253545233 |
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| cites | cdi_FETCH-LOGICAL-a394t-320c324126bbfaa31762a529cf4e5ec0235e9c266acc96ff652eefc9253545233 |
| container_end_page | 4538 |
| container_issue | 10 |
| container_start_page | 4526 |
| container_title | Journal of medicinal chemistry |
| container_volume | 59 |
| creator | Daniele, Simona La Pietra, Valeria Barresi, Elisabetta Di Maro, Salvatore Da Pozzo, Eleonora Robello, Marco La Motta, Concettina Cosconati, Sandro Taliani, Sabrina Marinelli, Luciana Novellino, Ettore Martini, Claudia Da Settimo, Federico |
| description | In glioblastoma multiforme (GBM), translocator protein (TSPO) and murine double minute (MDM)2/p53 complex represent two druggable targets. We recently reported the first dual binder 3 possessing a higher anticancer effect in GBM cells than the standards PK11195 1 or Nutlin-3 2 singularly applied. Herein, through a structure–activity relationship study, we developed derivatives 4–10 with improved potencies toward both TSPO and MDM2. As a result, compound 9: (i) reactivated the p53 functionality; (ii) inhibited the viability of two human GBM cells; (iii) impaired the proliferation of glioma cancer stem cells (CSCs), more resistant to chemotherapeutics and responsible of GBM recurrence; (iv) sensitized GBM cells and CSCs to the activity of temozolomide; (v) directed its effects preferentially toward tumor cells with respect to healthy ones. Thus, 9 may represent a promising cytotoxic agent, which is worthy of being further developed for a therapeutic approach against GBM, where the downstream p53 signaling is intact and TSPO is overexpressed. |
| doi_str_mv | 10.1021/acs.jmedchem.5b01767 |
| format | article |
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Med. Chem</addtitle><description>In glioblastoma multiforme (GBM), translocator protein (TSPO) and murine double minute (MDM)2/p53 complex represent two druggable targets. We recently reported the first dual binder 3 possessing a higher anticancer effect in GBM cells than the standards PK11195 1 or Nutlin-3 2 singularly applied. Herein, through a structure–activity relationship study, we developed derivatives 4–10 with improved potencies toward both TSPO and MDM2. As a result, compound 9: (i) reactivated the p53 functionality; (ii) inhibited the viability of two human GBM cells; (iii) impaired the proliferation of glioma cancer stem cells (CSCs), more resistant to chemotherapeutics and responsible of GBM recurrence; (iv) sensitized GBM cells and CSCs to the activity of temozolomide; (v) directed its effects preferentially toward tumor cells with respect to healthy ones. 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La Pietra, Valeria ; Barresi, Elisabetta ; Di Maro, Salvatore ; Da Pozzo, Eleonora ; Robello, Marco ; La Motta, Concettina ; Cosconati, Sandro ; Taliani, Sabrina ; Marinelli, Luciana ; Novellino, Ettore ; Martini, Claudia ; Da Settimo, Federico</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-a394t-320c324126bbfaa31762a529cf4e5ec0235e9c266acc96ff652eefc9253545233</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2016</creationdate><topic>Antineoplastic Agents - chemical synthesis</topic><topic>Antineoplastic Agents - chemistry</topic><topic>Antineoplastic Agents - pharmacology</topic><topic>Cell Proliferation - drug effects</topic><topic>Cell Survival - drug effects</topic><topic>Dipeptides - chemical synthesis</topic><topic>Dipeptides - chemistry</topic><topic>Dipeptides - pharmacology</topic><topic>Dose-Response Relationship, Drug</topic><topic>Drug Screening Assays, Antitumor</topic><topic>Glioblastoma - drug therapy</topic><topic>Glioblastoma - pathology</topic><topic>Humans</topic><topic>Models, Molecular</topic><topic>Molecular Structure</topic><topic>Proto-Oncogene Proteins c-mdm2 - antagonists & inhibitors</topic><topic>Proto-Oncogene Proteins c-mdm2 - metabolism</topic><topic>Receptors, GABA - metabolism</topic><topic>Structure-Activity Relationship</topic><topic>Tumor Cells, Cultured</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Daniele, Simona</creatorcontrib><creatorcontrib>La Pietra, Valeria</creatorcontrib><creatorcontrib>Barresi, Elisabetta</creatorcontrib><creatorcontrib>Di Maro, Salvatore</creatorcontrib><creatorcontrib>Da Pozzo, Eleonora</creatorcontrib><creatorcontrib>Robello, Marco</creatorcontrib><creatorcontrib>La Motta, Concettina</creatorcontrib><creatorcontrib>Cosconati, Sandro</creatorcontrib><creatorcontrib>Taliani, Sabrina</creatorcontrib><creatorcontrib>Marinelli, Luciana</creatorcontrib><creatorcontrib>Novellino, Ettore</creatorcontrib><creatorcontrib>Martini, Claudia</creatorcontrib><creatorcontrib>Da Settimo, Federico</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>Daniele, Simona</au><au>La Pietra, Valeria</au><au>Barresi, Elisabetta</au><au>Di Maro, Salvatore</au><au>Da Pozzo, Eleonora</au><au>Robello, Marco</au><au>La Motta, Concettina</au><au>Cosconati, Sandro</au><au>Taliani, Sabrina</au><au>Marinelli, Luciana</au><au>Novellino, Ettore</au><au>Martini, Claudia</au><au>Da Settimo, Federico</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Lead Optimization of 2‑Phenylindolylglyoxylyldipeptide Murine Double Minute (MDM)2/Translocator Protein (TSPO) Dual Inhibitors for the Treatment of Gliomas</atitle><jtitle>Journal of medicinal chemistry</jtitle><addtitle>J. Med. Chem</addtitle><date>2016-05-26</date><risdate>2016</risdate><volume>59</volume><issue>10</issue><spage>4526</spage><epage>4538</epage><pages>4526-4538</pages><issn>0022-2623</issn><eissn>1520-4804</eissn><notes>ObjectType-Article-1</notes><notes>SourceType-Scholarly Journals-1</notes><notes>ObjectType-Feature-2</notes><notes>content type line 23</notes><abstract>In glioblastoma multiforme (GBM), translocator protein (TSPO) and murine double minute (MDM)2/p53 complex represent two druggable targets. We recently reported the first dual binder 3 possessing a higher anticancer effect in GBM cells than the standards PK11195 1 or Nutlin-3 2 singularly applied. Herein, through a structure–activity relationship study, we developed derivatives 4–10 with improved potencies toward both TSPO and MDM2. As a result, compound 9: (i) reactivated the p53 functionality; (ii) inhibited the viability of two human GBM cells; (iii) impaired the proliferation of glioma cancer stem cells (CSCs), more resistant to chemotherapeutics and responsible of GBM recurrence; (iv) sensitized GBM cells and CSCs to the activity of temozolomide; (v) directed its effects preferentially toward tumor cells with respect to healthy ones. Thus, 9 may represent a promising cytotoxic agent, which is worthy of being further developed for a therapeutic approach against GBM, where the downstream p53 signaling is intact and TSPO is overexpressed.</abstract><cop>United States</cop><pub>American Chemical Society</pub><pmid>27050782</pmid><doi>10.1021/acs.jmedchem.5b01767</doi><tpages>13</tpages><oa>free_for_read</oa></addata></record> |
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| identifier | ISSN: 0022-2623 |
| ispartof | Journal of medicinal chemistry, 2016-05, Vol.59 (10), p.4526-4538 |
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| language | eng |
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| source | American Chemical Society:Jisc Collections:American Chemical Society Read & Publish Agreement 2022-2024 (Reading list) |
| subjects | Antineoplastic Agents - chemical synthesis Antineoplastic Agents - chemistry Antineoplastic Agents - pharmacology Cell Proliferation - drug effects Cell Survival - drug effects Dipeptides - chemical synthesis Dipeptides - chemistry Dipeptides - pharmacology Dose-Response Relationship, Drug Drug Screening Assays, Antitumor Glioblastoma - drug therapy Glioblastoma - pathology Humans Models, Molecular Molecular Structure Proto-Oncogene Proteins c-mdm2 - antagonists & inhibitors Proto-Oncogene Proteins c-mdm2 - metabolism Receptors, GABA - metabolism Structure-Activity Relationship Tumor Cells, Cultured |
| title | Lead Optimization of 2‑Phenylindolylglyoxylyldipeptide Murine Double Minute (MDM)2/Translocator Protein (TSPO) Dual Inhibitors for the Treatment of Gliomas |
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