Non-NAD-Like poly(ADP-Ribose) Polymerase-1 Inhibitors effectively Eliminate Cancer in vivo
The clinical potential of PARP-1 inhibitors has been recognized >10 years ago, prompting intensive research on their pharmacological application in several branches of medicine, particularly in oncology. However, natural or acquired resistance of tumors to known PARP-1 inhibitors poses a serious...
| Main Authors: | , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2016-11-01
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| Series: | EBioMedicine |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S235239641630456X |
| _version_ | 1819044218841071616 |
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| author | Colin Thomas Yingbiao Ji Niraj Lodhi Elena Kotova Aaron Dan Pinnola Konstantin Golovine Peter Makhov Kate Pechenkina Vladimir Kolenko Alexei V. Tulin |
| author_facet | Colin Thomas Yingbiao Ji Niraj Lodhi Elena Kotova Aaron Dan Pinnola Konstantin Golovine Peter Makhov Kate Pechenkina Vladimir Kolenko Alexei V. Tulin |
| author_sort | Colin Thomas |
| collection | DOAJ |
| description | The clinical potential of PARP-1 inhibitors has been recognized >10 years ago, prompting intensive research on their pharmacological application in several branches of medicine, particularly in oncology. However, natural or acquired resistance of tumors to known PARP-1 inhibitors poses a serious problem for their clinical implementation. Present study aims to reignite clinical interest to PARP-1 inhibitors by introducing a new method of identifying highly potent inhibitors and presenting the largest known collection of structurally diverse inhibitors. The majority of PARP-1 inhibitors known to date have been developed as NAD competitors. NAD is utilized by many enzymes other than PARP-1, resulting in a trade-off trap between their specificity and efficacy. To circumvent this problem, we have developed a new strategy to blindly screen a small molecule library for PARP-1 inhibitors by targeting a highly specific rout of its activation. Based on this screen, we present a collection of PARP-1 inhibitors and provide their structural classification. In addition to compounds that show structural similarity to NAD or known PARP-1 inhibitors, the screen identified structurally new non-NAD-like inhibitors that block PARP-1 activity in cancer cells with greater efficacy and potency than classical PARP-1 inhibitors currently used in clinic. These non-NAD-like PARP-1 inhibitors are effective against several types of human cancer xenografts, including kidney, prostate, and breast tumors in vivo. Our pre-clinical testing of these inhibitors using laboratory animals has established a strong foundation for advancing the new inhibitors to clinical trials. |
| first_indexed | 2024-12-21T10:09:11Z |
| format | Article |
| id | doaj.art-2dd741d05de3488380976c9c46ec0094 |
| institution | Directory Open Access Journal |
| issn | 2352-3964 |
| language | English |
| last_indexed | 2024-12-21T10:09:11Z |
| publishDate | 2016-11-01 |
| publisher | Elsevier |
| record_format | Article |
| series | EBioMedicine |
| spelling | doaj.art-2dd741d05de3488380976c9c46ec00942022-12-21T19:07:45ZengElsevierEBioMedicine2352-39642016-11-0113C909810.1016/j.ebiom.2016.10.001Non-NAD-Like poly(ADP-Ribose) Polymerase-1 Inhibitors effectively Eliminate Cancer in vivoColin ThomasYingbiao JiNiraj LodhiElena KotovaAaron Dan PinnolaKonstantin GolovinePeter MakhovKate PechenkinaVladimir KolenkoAlexei V. TulinThe clinical potential of PARP-1 inhibitors has been recognized >10 years ago, prompting intensive research on their pharmacological application in several branches of medicine, particularly in oncology. However, natural or acquired resistance of tumors to known PARP-1 inhibitors poses a serious problem for their clinical implementation. Present study aims to reignite clinical interest to PARP-1 inhibitors by introducing a new method of identifying highly potent inhibitors and presenting the largest known collection of structurally diverse inhibitors. The majority of PARP-1 inhibitors known to date have been developed as NAD competitors. NAD is utilized by many enzymes other than PARP-1, resulting in a trade-off trap between their specificity and efficacy. To circumvent this problem, we have developed a new strategy to blindly screen a small molecule library for PARP-1 inhibitors by targeting a highly specific rout of its activation. Based on this screen, we present a collection of PARP-1 inhibitors and provide their structural classification. In addition to compounds that show structural similarity to NAD or known PARP-1 inhibitors, the screen identified structurally new non-NAD-like inhibitors that block PARP-1 activity in cancer cells with greater efficacy and potency than classical PARP-1 inhibitors currently used in clinic. These non-NAD-like PARP-1 inhibitors are effective against several types of human cancer xenografts, including kidney, prostate, and breast tumors in vivo. Our pre-clinical testing of these inhibitors using laboratory animals has established a strong foundation for advancing the new inhibitors to clinical trials.http://www.sciencedirect.com/science/article/pii/S235239641630456XPARP-1PARP-1 inhibitorsHistone-dependent PARP-1 regulationPoly(ADP-ribose)Cancer cells |
| spellingShingle | Colin Thomas Yingbiao Ji Niraj Lodhi Elena Kotova Aaron Dan Pinnola Konstantin Golovine Peter Makhov Kate Pechenkina Vladimir Kolenko Alexei V. Tulin Non-NAD-Like poly(ADP-Ribose) Polymerase-1 Inhibitors effectively Eliminate Cancer in vivo EBioMedicine PARP-1 PARP-1 inhibitors Histone-dependent PARP-1 regulation Poly(ADP-ribose) Cancer cells |
| title | Non-NAD-Like poly(ADP-Ribose) Polymerase-1 Inhibitors effectively Eliminate Cancer in vivo |
| title_full | Non-NAD-Like poly(ADP-Ribose) Polymerase-1 Inhibitors effectively Eliminate Cancer in vivo |
| title_fullStr | Non-NAD-Like poly(ADP-Ribose) Polymerase-1 Inhibitors effectively Eliminate Cancer in vivo |
| title_full_unstemmed | Non-NAD-Like poly(ADP-Ribose) Polymerase-1 Inhibitors effectively Eliminate Cancer in vivo |
| title_short | Non-NAD-Like poly(ADP-Ribose) Polymerase-1 Inhibitors effectively Eliminate Cancer in vivo |
| title_sort | non nad like poly adp ribose polymerase 1 inhibitors effectively eliminate cancer in vivo |
| topic | PARP-1 PARP-1 inhibitors Histone-dependent PARP-1 regulation Poly(ADP-ribose) Cancer cells |
| url | http://www.sciencedirect.com/science/article/pii/S235239641630456X |
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