A novel small molecule inhibitor of p32 mitochondrial protein overexpressed in glioma
Abstract Background The mitochondrial protein p32 is a validated therapeutic target of cancer overexpressed in glioma. Therapeutic targeting of p32 with monoclonal antibody or p32-binding LyP-1 tumor-homing peptide can limit tumor growth. However, these agents do not specifically target mitochondria...
| Main Authors: | , , , , , , , |
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| Format: | Article |
| Language: | English |
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BMC
2017-10-01
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| Series: | Journal of Translational Medicine |
| Subjects: | |
| Online Access: | http://link.springer.com/article/10.1186/s12967-017-1312-7 |
| _version_ | 1819145307855781888 |
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| author | Venkata Yenugonda Natsuko Nomura Valentina Kouznetsova Igor Tsigelny Valentina Fogal Elmar Nurmemmedov Santosh Kesari Ivan Babic |
| author_facet | Venkata Yenugonda Natsuko Nomura Valentina Kouznetsova Igor Tsigelny Valentina Fogal Elmar Nurmemmedov Santosh Kesari Ivan Babic |
| author_sort | Venkata Yenugonda |
| collection | DOAJ |
| description | Abstract Background The mitochondrial protein p32 is a validated therapeutic target of cancer overexpressed in glioma. Therapeutic targeting of p32 with monoclonal antibody or p32-binding LyP-1 tumor-homing peptide can limit tumor growth. However, these agents do not specifically target mitochondrial-localized p32 and would not readily cross the blood–brain barrier to target p32-overexpressing gliomas. Identifying small molecule inhibitors of p32 overexpressed in cancer is a more rational therapeutic strategy. Thus, in this study we employed a pharmacophore modeling strategy to identify small molecules that could bind and inhibit mitochondrial p32. Methods A pharmacophore model of C1q and LyP-1 peptide association with p32 was used to screen a virtual compound library. A primary screening assay for inhibitors of p32 was developed to identify compounds that could rescue p32-dependent glutamine-addicted glioma cells from glutamine withdrawal. Inhibitors from this screen were analyzed for direct binding to p32 by fluorescence polarization assay and protein thermal shift. Affect of the p32 inhibitor on glioma cell proliferation was assessed by Alamar Blue assay, and affect on metabolism was examined by measuring lactate secretion. Results Identification of a hit compound (M36) validates the pharmacophore model. M36 binds directly to p32 and inhibits LyP-1 tumor homing peptide association with p32 in vitro. M36 effectively inhibits the growth of p32 overexpressing glioma cells, and sensitizes the cells to glucose depletion. Conclusions This study demonstrates a novel screening strategy to identify potential inhibitors of mitochondrial p32 protein overexpressed in glioma. High throughput screening employing this strategy has potential to identify highly selective, potent, brain-penetrant small molecules amenable for further drug development. |
| first_indexed | 2024-12-22T12:55:57Z |
| format | Article |
| id | doaj.art-199b2f3e7382454b8f7abe24e23d53dc |
| institution | Directory Open Access Journal |
| issn | 1479-5876 |
| language | English |
| last_indexed | 2024-12-22T12:55:57Z |
| publishDate | 2017-10-01 |
| publisher | BMC |
| record_format | Article |
| series | Journal of Translational Medicine |
| spelling | doaj.art-199b2f3e7382454b8f7abe24e23d53dc2022-12-21T18:25:06ZengBMCJournal of Translational Medicine1479-58762017-10-0115111210.1186/s12967-017-1312-7A novel small molecule inhibitor of p32 mitochondrial protein overexpressed in gliomaVenkata Yenugonda0Natsuko Nomura1Valentina Kouznetsova2Igor Tsigelny3Valentina Fogal4Elmar Nurmemmedov5Santosh Kesari6Ivan Babic7John Wayne Cancer Institute and Pacific Neuroscience Institute at Providence Saint John’s Health CenterJohn Wayne Cancer Institute and Pacific Neuroscience Institute at Providence Saint John’s Health CenterUniversity of California San DiegoUniversity of California San DiegoUniversity of California San DiegoJohn Wayne Cancer Institute and Pacific Neuroscience Institute at Providence Saint John’s Health CenterJohn Wayne Cancer Institute and Pacific Neuroscience Institute at Providence Saint John’s Health CenterJohn Wayne Cancer Institute and Pacific Neuroscience Institute at Providence Saint John’s Health CenterAbstract Background The mitochondrial protein p32 is a validated therapeutic target of cancer overexpressed in glioma. Therapeutic targeting of p32 with monoclonal antibody or p32-binding LyP-1 tumor-homing peptide can limit tumor growth. However, these agents do not specifically target mitochondrial-localized p32 and would not readily cross the blood–brain barrier to target p32-overexpressing gliomas. Identifying small molecule inhibitors of p32 overexpressed in cancer is a more rational therapeutic strategy. Thus, in this study we employed a pharmacophore modeling strategy to identify small molecules that could bind and inhibit mitochondrial p32. Methods A pharmacophore model of C1q and LyP-1 peptide association with p32 was used to screen a virtual compound library. A primary screening assay for inhibitors of p32 was developed to identify compounds that could rescue p32-dependent glutamine-addicted glioma cells from glutamine withdrawal. Inhibitors from this screen were analyzed for direct binding to p32 by fluorescence polarization assay and protein thermal shift. Affect of the p32 inhibitor on glioma cell proliferation was assessed by Alamar Blue assay, and affect on metabolism was examined by measuring lactate secretion. Results Identification of a hit compound (M36) validates the pharmacophore model. M36 binds directly to p32 and inhibits LyP-1 tumor homing peptide association with p32 in vitro. M36 effectively inhibits the growth of p32 overexpressing glioma cells, and sensitizes the cells to glucose depletion. Conclusions This study demonstrates a novel screening strategy to identify potential inhibitors of mitochondrial p32 protein overexpressed in glioma. High throughput screening employing this strategy has potential to identify highly selective, potent, brain-penetrant small molecules amenable for further drug development.http://link.springer.com/article/10.1186/s12967-017-1312-7Mitochondrial p32C1qBPGliomaMetabolismPharmacophore modeling |
| spellingShingle | Venkata Yenugonda Natsuko Nomura Valentina Kouznetsova Igor Tsigelny Valentina Fogal Elmar Nurmemmedov Santosh Kesari Ivan Babic A novel small molecule inhibitor of p32 mitochondrial protein overexpressed in glioma Journal of Translational Medicine Mitochondrial p32 C1qBP Glioma Metabolism Pharmacophore modeling |
| title | A novel small molecule inhibitor of p32 mitochondrial protein overexpressed in glioma |
| title_full | A novel small molecule inhibitor of p32 mitochondrial protein overexpressed in glioma |
| title_fullStr | A novel small molecule inhibitor of p32 mitochondrial protein overexpressed in glioma |
| title_full_unstemmed | A novel small molecule inhibitor of p32 mitochondrial protein overexpressed in glioma |
| title_short | A novel small molecule inhibitor of p32 mitochondrial protein overexpressed in glioma |
| title_sort | novel small molecule inhibitor of p32 mitochondrial protein overexpressed in glioma |
| topic | Mitochondrial p32 C1qBP Glioma Metabolism Pharmacophore modeling |
| url | http://link.springer.com/article/10.1186/s12967-017-1312-7 |
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