A small-molecule protein-protein interaction inhibitor of PARP1 that targets its BRCT domain
© 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim..
Poly(ADP-ribose)polymerase-1 (PARP1) is a BRCT-containing enzyme (BRCT = BRCA1 C-terminus) mainly involved in DNA repair and damage response and a validated target for cancer treatment. Small-molecule inhibitors that target the PARP1 catalytic domain have been actively pursued as anticancer drugs, but are potentially problematic owing to a lack of selectivity. Compounds that are capable of disrupting protein-protein interactions of PARP1 provide an alternative by inhibiting its activities with improved selectivity profiles. Herein, by establishing a high-throughput microplate-based assay suitable for screening potential PPI inhibitors of the PARP1 BRCT domain, we have discovered that (±)-gossypol, a natural product with a number of known biological activities, possesses novel PARP1 inhibitory activity both in vitro and in cancer cells and presumably acts through disruption of protein-protein interactions. As the first known cell-permeable small-molecule PPI inhibitor of PAPR1, we further established that (-)-gossypol was likely the causative agent of PARP1 inhibition by promoting the formation of a 1:2 compound/PARP1 complex by reversible formation of a covalent imine linkage.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2015 |
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| Erschienen: |
2015 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:54 |
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| Enthalten in: |
Angewandte Chemie (International ed. in English) - 54(2015), 8 vom: 16. Feb., Seite 2515-9 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Na, Zhenkun [VerfasserIn] |
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| Links: |
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| Anmerkungen: |
Date Completed 27.10.2015 Date Revised 19.11.2015 published: Print-Electronic Citation Status MEDLINE |
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| doi: |
10.1002/anie.201410678 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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NLM245121080 |
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| 520 | |a Poly(ADP-ribose)polymerase-1 (PARP1) is a BRCT-containing enzyme (BRCT = BRCA1 C-terminus) mainly involved in DNA repair and damage response and a validated target for cancer treatment. Small-molecule inhibitors that target the PARP1 catalytic domain have been actively pursued as anticancer drugs, but are potentially problematic owing to a lack of selectivity. Compounds that are capable of disrupting protein-protein interactions of PARP1 provide an alternative by inhibiting its activities with improved selectivity profiles. Herein, by establishing a high-throughput microplate-based assay suitable for screening potential PPI inhibitors of the PARP1 BRCT domain, we have discovered that (±)-gossypol, a natural product with a number of known biological activities, possesses novel PARP1 inhibitory activity both in vitro and in cancer cells and presumably acts through disruption of protein-protein interactions. As the first known cell-permeable small-molecule PPI inhibitor of PAPR1, we further established that (-)-gossypol was likely the causative agent of PARP1 inhibition by promoting the formation of a 1:2 compound/PARP1 complex by reversible formation of a covalent imine linkage | ||
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| 700 | 1 | |a Ng, Shukie |e verfasserin |4 aut | |
| 700 | 1 | |a Pan, Sijun |e verfasserin |4 aut | |
| 700 | 1 | |a Lee, Jun-Seok |e verfasserin |4 aut | |
| 700 | 1 | |a Shen, Han-Ming |e verfasserin |4 aut | |
| 700 | 1 | |a Yao, Shao Q |e verfasserin |4 aut | |
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